Next Article in Journal
Cranial Neuropathy Secondary to Carotid Artery Dissection: Clinical Features and Long-Term Outcomes
Previous Article in Journal
Reliability and Validity of the Japanese Version of the Multidimensional Evaluation Scale for Patient Impression Change (MPIC): A Brief Tool for Multidimensional Assessment in Interdisciplinary Pain Management
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 14
Issue 19
10.3390/jcm14196853
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Targeted Therapies Modulating Mesenchymal–Epithelial Transition-Linked Oncogenic Signaling in the Tumor Microenvironment: Comparative Profiling of Capmatinib, Bemcentinib, and Galunisertib

by
Piotr Kawczak
1,*,
Igor Jarosław Feszak
2 and
Tomasz Bączek
1,3
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Gdańsk, 80-416 Gdańsk, Poland
2
Institute of Health Sciences, Pomeranian University in Słupsk, 76-200 Słupsk, Poland
3
Department of Nursing and Medical Rescue, Institute of Health Sciences, Pomeranian University in Słupsk, 76-200 Słupsk, Poland
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(19), 6853; https://doi.org/10.3390/jcm14196853
Submission received: 29 August 2025 / Revised: 21 September 2025 / Accepted: 26 September 2025 / Published: 27 September 2025
(This article belongs to the Special Issue Tumor Microenvironment—Current Status and Therapeutic Targets)
Browse Figures
Versions Notes

Abstract

The mesenchymal–epithelial transition/plasticity (MET/EMP) axis is a key regulator of tumor development, cancer progression, and resistance to therapy, making it an attractive target for intervention. This review highlights strategies to modulate MET/EMP using three representative agents—capmatinib, bemcentinib, and galunisertib—each acting on distinct signaling pathways. Capmatinib is a selective MET tyrosine kinase inhibitor with notable efficacy in non-small cell lung cancer harboring MET exon 14 skipping mutations. Bemcentinib blocks AXL receptor tyrosine kinase, interfering with AXL/GAS6 signaling that promotes tumor survival, metastasis, and therapeutic resistance. Galunisertib inhibits TGF-β signaling, reducing epithelial–mesenchymal transition (EMT), immune evasion, and metastatic potential. We discuss their mechanisms of action, therapeutic applications, and current clinical progress. Although these targeted therapies show potential to overcome resistance and improve patient outcomes, challenges remain due to the complex regulation of EMP. Future directions focus on refining combination strategies and advancing personalized approaches to enhance efficacy across multiple cancer types.

1. Introduction

Cancer continues to be one of the primary causes of morbidity and mortality worldwide, with metastasis responsible for nearly 90% of cancer-related deaths [1]. Metastatic progression arises from the dissemination of tumor cells from primary tumors to distant organs, a process driven by dynamic and reversible alterations in cellular phenotype and behavior [2]. At the core of this adaptability is epithelial–mesenchymal plasticity (EMP), which encompasses a continuum between epithelial and mesenchymal states, including both epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) [3,4,5].
EMP is clinically critical, as it enables tumor cells to lose epithelial polarity and adhesion [6,7], acquire motility and invasiveness [8,9], and penetrate surrounding tissues [10], thereby facilitating dissemination, intravasation, survival in circulation, immune evasion, and therapy resistance. Conversely, MET—the reacquisition of epithelial features—is frequently required for metastatic colonization and outgrowth at distant sites [11,12,13]. Importantly, MET is an actively regulated process with direct consequences for disease progression and patient outcomes [14]. Beyond metastasis, EMP equips tumor cells to adapt to microenvironmental stressors, evade immune detection, and resist therapy [15]. Although the molecular mechanisms underlying EMT are well characterized, MET remains comparatively underexplored [16,17], despite its clear therapeutic importance.
Several signaling pathways, including TGF-β [18,19], HGF/MET, and AXL [20,21,22], are central regulators of EMP [23,24,25]. Because these pathways govern both EMT and MET, targeting them represents a promising strategy to modulate EMP and potentially improve clinical outcomes. Three targeted inhibitors have emerged as leading EMP modulators: capmatinib (a MET inhibitor), bemcentinib (an AXL inhibitor), and galunisertib (a TGF-β receptor I kinase inhibitor). Bemcentinib blocks AXL, a major EMT driver linked to immune evasion and resistance, thereby promoting MET and enhancing responsiveness to immune checkpoint blockade [26,27,28,29,30,31,32]. Galunisertib inhibits TGF-β receptor I kinase, counteracting TGF-β–induced EMT, restoring epithelial traits, and sensitizing tumors to chemotherapy and immunotherapy [33,34,35,36,37]. Capmatinib suppresses aberrant MET-driven signaling, often activated by MET exon 14 skipping mutations that promote EMT, metastasis, and resistance, thereby reducing EMT and metastatic progression in non-small-cell lung cancer (NSCLC) and showing early improvements in progression-free survival (PFS) in MET-altered tumors [38,39,40,41,42,43,44].
Despite encouraging progress, significant challenges remain in translating EMP-targeted therapies into clinical practice. The heterogeneity of EMP complicates biomarker development and patient stratification [45,46], while compensatory signaling reduces the efficacy of single-agent approaches [47]. Resistance mechanisms, such as secondary mutations and pathway reactivation, further undermine therapeutic durability [48,49,50]. Additionally, because mesenchymal-like states can confer context-dependent survival benefits, the timing and setting of MET induction must be carefully optimized [14,51,52].
Emerging technologies—including single-cell RNA sequencing [53,54,55], lineage tracing [56,57], and patient-derived organoid models [58,59]—are advancing the mapping of EMP’s spatiotemporal dynamics and revealing additional regulatory mechanisms. Epigenetic modifiers [60], microRNAs [61], long non-coding RNAs [62], and tumor microenvironment (TME) components [63] also influence EMP-driven metastasis and therapeutic response.
Therapeutic induction of MET may offer advantages beyond simply reversing EMT. Whereas EMT promotes dissemination, MET facilitates epithelial re-differentiation, restricts metastatic progression, and enhances therapy sensitivity [37,64]. EMT is now understood as a continuum, generating hybrid epithelial/mesenchymal states [65] that support collective migration, immune evasion [66], and drug resistance [67,68]. Targeting these intermediate states through MET induction may destabilize plasticity, mitigate resistance, and improve clinical outcomes [69].
In this review, we synthesize current understanding of MET as a dynamic and targetable process in metastasis. We highlight capmatinib, bemcentinib, and galunisertib as case studies of EMP-modulating therapies, focusing on their mechanisms, therapeutic potential, and the obstacles that remain for clinical translation.
Figure 1 illustrates the EMT spectrum, hybrid states—molecular regulators and therapeutic timing for EMT/MET modulation throughout tumor progression taking into account similarities and differences of capmatinib, bemcentinib and galunisertib, while Table 1 summarizes the involvement of epithelial–mesenchymal transition transcription factors (EMT-TFs) in the regulation of tumour cell motility (TCM).

2. Capmatinib–MET Inhibitor

Capmatinib (INC280) is an orally bioavailable, selective type Ib inhibitor of the MET receptor tyrosine kinase, a critical oncogenic driver involved in cellular proliferation, survival, migration, and invasion [71].
Figure 2 illustrates the chemical structure of capmatinib.
The MET proto-oncogene encodes a receptor activated by hepatocyte growth factor (HGF), triggering PI3K/AKT, RAS/MAPK, and STAT signaling cascades [72]. Aberrant MET activation promotes tumorigenesis through multiple mechanisms, including exon 14 skipping mutations [73,74], gene amplification [75,76], protein overexpression [77,78], and gene fusions [79,80], particularly in NSCLC. MET exon 14 skipping mutations impair receptor degradation, sustaining oncogenic signaling, and are most frequently detected in NSCLC [81,82,83,84,85], though also observed in gastric [86], renal [87], head and neck [88], and hepatocellular carcinomas (HCCs) [89,90,91,92,93]. Beyond NSCLC, expression of the L1-MET retrotransposon has been linked to bladder and liver cancers [73], colorectal cancer [74], and aggressive breast cancers [75]. Capmatinib binds the ATP-binding pocket of MET, blocking autophosphorylation and downstream activation [24,94,95]. It is administered orally at 400 mg twice daily, metabolized primarily via CYP3A4 and aldehyde oxidase, with a terminal half-life of ~6 h and steady-state levels reached within 15 days [96,97,98]. Importantly, capmatinib penetrates the blood–brain barrier, enabling activity against CNS metastases in NSCLC [99,100].
Preclinical studies demonstrated that capmatinib effectively inhibits MET-driven signaling, reduces EMT, and curtails metastatic spread. Synergistic activity has been shown when combined with inhibitors of compensatory RTKs such as EGFR and AXL [101], as well as with epigenetic modulators like HDAC and DNMT inhibitors that reverse EMT-associated transcriptional programs [102,103].
Clinically, the most notable evidence for capmatinib comes from the phase II GEOMETRY mono-1 trial. In this study, treatment-naïve NSCLC patients harboring MET exon 14 skipping mutations achieved a 68% objective response rate (ORR), while previously treated patients achieved a 41% ORR, with median response durations of 12.6 and 9.7 months, respectively [104,105]. These results supported the accelerated FDA approval of capmatinib (Tabrecta®) in May 2020 for metastatic NSCLC with MET exon 14 skipping mutations [106,107,108]. Ongoing studies are evaluating capmatinib in combination with other targeted therapies, such as EGFR inhibitors, and with immunotherapy, to overcome resistance and expand clinical indications [109,110,111]. Early-phase trials are also exploring its role in HCC, glioblastoma, prostate cancer, and papillary renal cell carcinoma, all of which harbor MET pathway aberrations [112,113,114,115,116,117].
Clinically, capmatinib is now established as a first-line targeted therapy for metastatic NSCLC with MET exon 14 skipping mutations, where it produces significantly improved survival compared to chemotherapy [118,119]. Its ability to penetrate the CNS is particularly important given the prevalence of brain metastases in advanced NSCLC [100,109]. At present, evidence largely derives from single-arm trials rather than randomized controlled trials, but outcomes consistently demonstrate durable responses and manageable safety. Expanding applications in other MET-driven cancers remain under active investigation [112,113,114,115,116,117].
Resistance to capmatinib arises through multiple mechanisms. Secondary MET kinase domain mutations, particularly D1228 and Y1230, reduce inhibitor binding and account for ~5–15% of resistance events in MET-driven NSCLC [120,121,122,123]. Additional mechanisms include bypass signaling via EGFR, AXL, HER3, and FGFR1 [124,125,126,127,128], as well as EMT-driven plasticity and epigenetic reprogramming that sustain mesenchymal phenotypes [129,130,131]. Therapeutic strategies to overcome resistance include combining capmatinib with AXL inhibitors such as bemcentinib (NCT04811176) or EGFR inhibitors such as osimertinib (NCT05468697), both of which have shown promising preliminary results with manageable toxicity and encouraging disease control rates [99,132]. Epigenetic approaches, including HDAC and DNMT inhibition, have also been shown to resensitize resistant cells by reversing EMT-associated transcriptional programs [102,103].
Capmatinib’s development highlights the potential role of biomarker-guided therapy in advancing precision oncology, though its broader impact will require further clinical validation [133,134]. Ongoing efforts focus on expanding its indications [135], refining patient selection [136], addressing acquired resistance [137], and implementing multidisciplinary care models to optimize outcomes [138,139,140].
Figure 3 depicts the HGF/MET signaling cascade and capmatinib’s mechanism of inhibition, while Table 2 outlines selected cytoplasmic MET inhibitors and their mechanisms.

3. Bemcentinib–AXL Inhibitor

Bemcentinib (BGB324, R428) is a highly selective, orally bioavailable small-molecule inhibitor targeting AXL, a receptor tyrosine kinase of the TAM family (TYRO3, AXL, MER) [143,144,145].
Figure 4 illustrates the chemical structure of bemcentinib.
AXL regulates proliferation, survival, migration, immune modulation, and lymphangiogenesis [146,147]. Its activation by the ligand GAS6 induces receptor dimerization and autophosphorylation, initiating PI3K/AKT, MAPK/ERK, and NF-κB signaling pathways that drive tumor progression, metastasis, and immune evasion [50,148]. Unlike TGF-β–driven EMT, which primarily involves SMAD-dependent transcriptional repression, AXL promotes EMT through sustained PI3K/AKT, NF-κB, and STAT3 signaling [149,150,151]. This route fosters phenotypic plasticity, therapy resistance, and stable mesenchymal states that are less reversible [4].
AXL frequently functions as a bypass resistance mechanism in cancers exposed to EGFR, VEGFR, and BRAF inhibitors, where therapeutic pressure induces AXL upregulation and compensatory survival signaling [150,151]. Preclinical studies show that pharmacological inhibition of AXL reverses resistance phenotypes and restores sensitivity to targeted agents [143]. Aberrant AXL signaling is implicated in NSCLC, breast cancer, AML, pancreatic cancer, and other malignancies, with overexpression correlating with poor prognosis and metastatic potential [150,152]. Beyond oncology, AXL activity contributes to fibrotic diseases, motivating trials in chronic kidney disease [153]. Bemcentinib exerts its effects by selectively binding the ATP-binding pocket of AXL, blocking autophosphorylation and downstream signaling [154,155]. This inhibits tumor proliferation, invasion, and metastasis, while promoting EMT reversal [156,157]. It also remodels the TME, enhancing dendritic cell activity, reducing regulatory T cells, and improving responsiveness to immune checkpoint blockade [158,159].
Developed by BerGenBio ASA in the mid-2010s [160,161], bemcentinib demonstrated potent AXL inhibition and antitumor activity in preclinical NSCLC and breast cancer models, both as monotherapy and in combination with other drugs [162,163]. In NSCLC, AXL blockade restored sensitivity to EGFR inhibitors by preventing compensatory survival signaling [164,165]. Early-phase clinical trials established favorable tolerability and preliminary efficacy in AXL-overexpressing malignancies [166,167]. In the phase II ACHILES trial, bemcentinib combined with docetaxel improved PFS and response rates compared to docetaxel alone in treatment-resistant NSCLC [168,169,170,171].
Beyond NSCLC, bemcentinib is in clinical development for AML, pancreatic and gastric cancers, HCC, mantle cell lymphoma, melanoma, endometrial cancer, rhabdomyosarcoma, CNS tumors, and myeloproliferative neoplasms [172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190]. Administered orally once daily, it has favorable pharmacokinetics characterized by rapid absorption, high bioavailability, and hepatic metabolism via CYP3A4, requiring monitoring for drug–drug interactions [191,192,193,194]. Steady-state plasma concentrations are achieved within days, ensuring sustained AXL inhibition [195,196]. Target engagement is confirmed in biopsies via reduced phosphorylated AXL levels [197,198]. Combination studies with immune checkpoint inhibitors such as pembrolizumab and nivolumab highlight its immunomodulatory potential [199,200].
The safety profile of bemcentinib is manageable. Common toxicities include fatigue, nausea, diarrhea, and mild transaminase elevations [201,202]. Less frequent but notable toxicities include hepatotoxicity and pneumonitis, requiring monitoring [203,204]. Grade 3 ALT/AST elevations have been reported [177,205], while gastrointestinal effects are usually mild [192,206]. Rare events include rash, hypersensitivity, and MRONJ [207,208,209]. Combination use with immune checkpoint inhibitors can lead to immune-related adverse events [210,211], and reproductive safety precautions are warranted [155,212]. Bemcentinib has been granted FDA Fast Track designation for patients with STK11-mutant metastatic NSCLC, a subgroup with poor response to other therapies [213,214,215,216].
Despite its promise, acquired resistance to bemcentinib remains a challenge. Compensatory signaling through parallel pathways or AXL kinase domain mutations can limit efficacy [49,217,218]. Predictive biomarkers are therefore needed, with candidates including AXL expression by IHC, circulating GAS6 levels, mesenchymal gene signatures, and ctDNA [219,220]. Emerging data suggest survival benefits in refractory cancers such as NSCLC and AML [173,221]. Optimizing its use will require biomarker-driven patient selection, multidisciplinary care, and toxicity management [191,222].
Table 3 outlines therapeutic strategies targeting AXL activation to inhibit EMT and overcome drug resistance.
Bemcentinib demonstrates efficacy across AXL-dysregulated cancers, with oral bioavailability and a tolerable safety profile supporting integration into standard therapy [224,225,226]. Ongoing studies aim to overcome resistance, broaden indications, and define its immunomodulatory roles beyond oncology [227]. As a first-in-class AXL inhibitor, bemcentinib exemplifies precision oncology by targeting tumor-intrinsic AXL signaling while modulating the immune microenvironment [228,229]. Its adoption will likely depend on rational combinations and resistance management, with preliminary evidence suggesting it may have activity relevant to both tumor biology and immune evasion, though confirmation in broader clinical settings is still needed [230,231,232,233,234,235,236,237].
Figure 5 depicts the molecular mechanism of action of bemcentinib.

4. Galunisertib–TGF-β Inhibitor

Galunisertib (LY2157299 monohydrate) is a selective, orally bioavailable inhibitor of transforming growth factor-beta receptor type I (TGF-βRI/ALK5), developed by Eli Lilly for oncology applications [239].
Figure 6 illustrates the chemical structure of galunisertib.
Its mechanism targets the canonical TGF-β pathway, in which ligand binding to type II receptors triggers phosphorylation of TGF-βRI, activating SMAD2/3 and their association with SMAD4 to form a transcriptionally active complex [240,241,242]. This complex regulates gene expression programs that control proliferation, differentiation, immune responses, and extracellular matrix remodeling [243,244]. In early tumorigenesis, TGF-β signaling exerts tumor-suppressive effects through induction of growth arrest and apoptosis by activating CDK inhibitors such as p15INK4b and p21CIP1 while repressing oncogenes like c-MYC [40,245]. As cancers progress, however, genetic and epigenetic alterations such as TP53 or PTEN loss, oncogenic Ras activation, and microenvironmental factors reprogram TGF-β into a pro-tumorigenic driver of invasion, immune evasion, and EMT via SMAD-dependent and non-canonical PI3K/AKT, MAPK, and Rho GTPase pathways [149,246].
Table 4 provides an overview of the TGFβ signaling pathway.
Galunisertib competitively occupies the ATP-binding pocket of TGF-βRI, blocking kinase activity and preventing SMAD2/3 phosphorylation [248,249,250,251]. By selectively inhibiting this receptor, galunisertib suppresses transcriptional programs that promote tumor progression while sparing many physiological TGF-β functions [252]. Preclinical models across diverse tumor types demonstrated that galunisertib reduces TGF-β signaling, tumor growth, and metastasis [253,254,255,256,257,258,259,260,261]. These findings translated into early-phase trials that confirmed tolerability, characterized pharmacokinetics, and revealed preliminary antitumor activity in biomarker-enriched patient populations [262,263].
In HCC, galunisertib downregulates VEGF, reduces angiogenesis, and suppresses hypoxia-driven pathways by decreasing TGF-β1 activity, hypoxia-inducible factor-1α (HIF-1α), and VEGF protein expression [264,265,266,267,268]. Within TGF-β–enriched (TMEs), galunisertib reduces fibrosis, EMT-related gene expression, and immune evasion, supporting disease stabilization in advanced HCC [269,270,271,272]. In glioblastoma, combining galunisertib with temozolomide and radiotherapy enhanced responses partly by modulating immunosuppressive stroma [273,274,275]. In pancreatic cancer, galunisertib disrupted tumor–stroma interactions, potentiating chemotherapy [276,277,278]. Ongoing trials in NSCLC are exploring galunisertib with immune checkpoint inhibitors and cytotoxics [279,280], while additional studies are underway in colorectal, breast, and melanoma cancers [281,282,283,284].
Beyond oncology, TGF-β signaling regulates fibroblast activation, EMT, and chronic inflammation, linking it to fibrotic diseases such as idiopathic pulmonary fibrosis, diabetic nephropathy, Crohn’s disease, and myocardial fibrosis [285,286,287,288,289,290]. These contexts mirror desmoplastic stroma in pancreatic ductal adenocarcinoma, HCC, and other solid tumors, characterized by excessive extracellular matrix deposition and immune exclusion. Inhibition of TGF-β signaling attenuates fibroblast activation, normalizes ECM, and reduces collagen accumulation, thereby improving perfusion and immune infiltration. Small-molecule inhibitors like galunisertib and vactosertib demonstrate antifibrotic and stroma-modulatory activity in both fibrotic and tumor-bearing models [291,292,293,294,295], providing a strong rationale for combining TGF-β blockade with immune checkpoint inhibitors or cytotoxics to enhance efficacy.
Galunisertib is generally well tolerated, with manageable toxicities including gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia), fatigue, mild hematologic effects, and transient liver enzyme elevations [296,297,298,299]. Initial concerns about cardiac toxicity, including QT prolongation and reduced LVEF, were mitigated by monitoring, but dose-limiting cardiotoxicity remained a constraint. Rare immune-related adverse events occurred when combined with checkpoint inhibitors [300,301]. Pharmacokinetic limitations also posed challenges: a short half-life of 4–6 h required twice-daily dosing, while plasma exposure above ~300 mg/day was associated with increased cardiac toxicity [262,302].
Despite promising mechanisms, clinical efficacy was modest. In a phase II HCC trial, galunisertib monotherapy achieved only a 5% response rate and median PFS of 2.7 months, failing to improve overall survival compared to sorafenib [303]. In pancreatic cancer, its combination with gemcitabine yielded an 11% response rate and median PFS of 3.6 months [304]. Most studies lacked validated biomarker-driven stratification, limiting the identification of responsive subgroups.
The clinical development of galunisertib underscores the complexity of TGF-β as a dual tumor suppressor and promoter. While its pharmacological inhibition showed proof of concept for targeting EMT, angiogenesis, and fibrosis in cancer, challenges with pharmacokinetics, safety, and lack of predictive biomarkers restricted its impact. Lessons from galunisertib inform the design of next-generation TGF-βRI inhibitors, highlighting the need for optimized drug properties, biomarker-guided patient selection, and rational combination regimens to realize the therapeutic potential of TGF-β pathway blockade.
Figure 7 illustrates the mechanism of action of galunisertib.

5. Future Perspectives and Clinical Implications in EMP Modulation

Key limitations of galunisertib—namely its short half-life necessitating intermittent dosing, the occurrence of cardiac toxicities, and the absence of validated predictive biomarkers—have guided the development of more advanced therapeutic strategies [248,249,250,251]. One such innovation is the design of bifunctional molecules like bintrafusp alfa (M7824), which simultaneously blocks PD-L1 and sequesters TGF-β ligands. This dual mechanism represents a refined therapeutic approach, with early-phase trials in NSCLC and biliary tract cancers reporting ORRs of 15–20% and median PFS of 2–4 months [306]. Compared with first-generation inhibitors, bintrafusp alfa has demonstrated improved pharmacokinetics and distinctive immunomodulatory effects.
Parallel efforts are focused on next-generation TGF-βRI inhibitors with greater selectivity and tolerability. Vactosertib (TEW-7197), an orally bioavailable ALK5 inhibitor, counteracts TGF-β–driven EMT and immune suppression and is currently under evaluation in combination with chemotherapy and immune checkpoint inhibitors [307,308]. Clinical programs exploring vactosertib-based regimens aim to enhance pharmacodynamic efficacy while minimizing off-target toxicities [309]. Similarly, LY3200882, another next-generation small-molecule inhibitor, offers improved pharmacokinetic and safety profiles and is in clinical testing for glioblastoma and other solid tumors [310,311]. Together, bifunctional TGF-β traps and selective TGF-βRI inhibitors exemplify a strategic evolution in pathway modulation, informed directly by clinical and pharmacologic lessons from galunisertib.
The MET, AXL, and TGF-β signaling pathways converge into a context-dependent network governing EMP, tumor progression, and therapeutic resistance. In vitro studies show that TGF-β upregulates AXL to stabilize mesenchymal states, while MET activation facilitates colonization during metastasis [125,148]. This has established a canonical model where TGF-β and AXL drive EMT and invasion, whereas MET promotes epithelial re-differentiation at metastatic sites.
However, in vivo and clinical evidence suggests this model is overly simplistic. Under hypoxic conditions or in stiff extracellular matrices, MET activation has been shown to sustain mesenchymal transcriptional programs, motility, and invasiveness, rather than inducing epithelial reversion [101,122]. These findings highlight that EMT/MET dynamics are highly context dependent, shaped not only by intrinsic signaling but also by biomechanical and metabolic cues within the TME. Untangling these context-specific influences is essential for translating preclinical data into clinical impact.
MET, AXL, and TGF-β converge on PI3K/AKT, MAPK, and STAT pathways, forming feedback loops that reinforce tumor plasticity and resistance, while hypoxia, inflammatory cytokines, and stromal inputs further amplify partial EMT states and immunosuppressive niches [247,257]. Yet, much of this understanding arises from 2D culture systems that treat EMT as binary, overlooking hybrid phenotypes and spatial heterogeneity uncovered by single-cell and spatial transcriptomics [245,256]. These limitations restrict translational fidelity and underscore the need for models that capture tumor architecture and microenvironmental complexity.
Beyond plasticity, this signaling triad directly fosters immune evasion. TGF-β excludes cytotoxic T-cell infiltration and expands regulatory T cells, while AXL upregulates PD-L1 and suppresses antigen presentation [42,286]. Mesenchymal-like tumor cells further secrete immunosuppressive cytokines, collectively establishing an immune-evasive TME that compromises immunotherapy efficacy.
Therapeutic strategies are therefore moving toward dual targeting of EMT/MET pathways and immunosuppressive signaling. Ongoing trials are investigating combinations of galunisertib (TGF-β inhibition), bemcentinib (AXL inhibition), and capmatinib (MET inhibition) with immune checkpoint blockade, aiming to overcome resistance and improve patient outcomes.
Looking ahead, integration of EMT-targeting agents with immunotherapy is expected to become more systematic. Agents such as capmatinib, bemcentinib, and galunisertib hold potential to relieve immunosuppressive pressures and sensitize tumors to checkpoint blockade [42,286,306]. Liquid biopsy biomarkers—including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and EMT-associated extracellular vesicles—offer minimally invasive means of tracking EMT dynamics, guiding patient selection, and monitoring treatment responses [117,219,256,312]. Emerging model systems, such as organoids and single-cell platforms, are becoming indispensable tools to interrogate tumor heterogeneity, hybrid states, and context-specific drug effects [53,245,269,313].
Patient populations most likely to benefit from EMT-targeting approaches include those with fibrotic, TGF-β–rich tumors (e.g., HCC, PDAC, NSCLC), patients resistant to immunotherapy due to T-cell exclusion, and tumors with high EMT-TF expression signatures detected via liquid biopsy or transcriptomic profiling [256,269,306]. Capmatinib is particularly suited to MET-driven subsets such as NSCLC with MET exon 14 skipping mutations or MET amplification [38,41,44]. Bemcentinib may benefit AXL-overexpressing tumors associated with resistance and immune evasion [50,142,145]. Galunisertib and newer TGF-βRI inhibitors are promising for fibrotic and TGF-β–driven cancers, where they can remodel stroma, reverse EMT, and restore immune infiltration, especially in combination with chemotherapy or immunotherapy [239,243,269].
Altogether, this integrated paradigm emphasizes precision oncology: combining EMT-targeting agents with immune modulation, guided by dynamic biomarker assessments and advanced preclinical models, to optimize patient-specific efficacy and overcome adaptive resistance [247,257,306].
Table 5 summarizes representative targeted small-molecule inhibitors of EMT-related pathways in cancer therapy, including capmatinib, bemcentinb, and galunisertib.

6. Conclusions

MET is a fundamental biological process with broad implications for targeted cancer therapy. The reciprocal interplay between EMT and MET underlies cellular plasticity, driving both metastatic progression and therapeutic resistance. Whereas EMT enables local invasion and dissemination, MET is essential for metastatic colonization and expansion at distant sites. This bidirectional adaptability highlights the therapeutic potential of MET modulation within a comprehensive oncologic framework.
Agents such as galunisertib, capmatinib, and bemcentinib illustrate complementary strategies for targeting MET-related pathways. Galunisertib inhibits TGF-βRI, attenuating a key EMT-inducing signal and indirectly favoring MET. Capmatinib blocks c-Met receptor tyrosine kinase, disrupting survival and EMT-associated signaling. Bemcentinib targets AXL, reducing mesenchymal traits and overcoming resistance. Despite distinct mechanisms, these agents converge on the principle that restraining EMP can limit plasticity and sensitize tumors to treatment.
Nonetheless, major challenges remain. Most clinical trials lack biomarker-driven designs to identify patients most likely to benefit from EMP-targeting agents. Longitudinal tracking of EMP dynamics in patients is limited, constraining insights into how plasticity evolves under therapeutic pressure. Resistance mechanisms, including pathway crosstalk and adaptive reprogramming, continue to compromise the durability of these strategies.
Future progress will require addressing these gaps. Incorporating EMP modulation into trial endpoints may offer more precise measures of therapeutic benefit beyond survival outcomes. Rational combinations—such as EMP-targeting agents with immunotherapy, chemotherapy, or anti-angiogenic drugs—hold promise for overcoming compensatory resistance. The development of predictive biomarkers, including EMP-specific molecular signatures, will be critical for patient stratification and treatment personalization.
Emerging technologies such as single-cell sequencing, real-time molecular profiling, and patient-derived models will deepen understanding of EMP heterogeneity and temporal dynamics. Novel delivery approaches, including nanoparticle-based systems, may enhance the specificity and tolerability of MET inhibitors.
Overall, MET represents a vital yet underutilized therapeutic axis in oncology. By closing current knowledge gaps and strategically integrating EMP-targeted interventions into precision medicine, MET-directed therapies have the potential to play a central role in improving outcomes and survival.

Author Contributions

Conceptualization, T.B. and P.K.; writing—original draft preparation, P.K.; writing—review and editing, P.K., I.J.F. and T.B.; visualization P.K.; supervision, T.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AKTProtein kinase B
ALKAnaplastic lymphoma kinase
ALK5Activin receptor-like kinase 5
ALTAlanine aminotransferase
AMLAcute myeloid leukemia
ASTAspartate aminotransferase
ASolTAdvanced Solid Tumors
ATPAdenosine triphosphate
AXLAXL receptor tyrosine kinase
bHLHBasic helix–loop–helix
CDH1Gene encoding E-cadherin
CDK(s)Cyclin-dependent kinase(s)
CIP1CDK-interacting protein 1 (p21CIP1)
CKDChronic kidney disease
CNSCentral nervous system
CRCColorectal cancer
CRC/RCColorectal and rectal cancers
ctDNACirculating tumor DNA
CTCsCirculating tumor cells
CYP3A4Cytochrome P450 3A4
DNADeoxyribonucleic acid
DNMTDNA methyltransferase
ECMExtracellular matrix
EGF(R)Epidermal growth factor (receptor)
EMPEpithelial–mesenchymal plasticity
EMTEpithelial–mesenchymal transition
EMT TFsEpithelial–mesenchymal transition transcription factors
ERK/ERKsExtracellular signal-regulated kinase(s)
FAKFocal adhesion kinase
FGFR1Fibroblast growth factor receptor 1
GAB1GRB2-associated binder 1
GAS6Growth arrest–specific 6
GBMGlioblastoma
GRB2Growth factor receptor–bound protein 2
GSK3Glycogen synthase kinase 3
GTPaseGuanosine triphosphatase
HCCHepatocellular carcinoma
HDACHistone deacetylase
HGFHepatocyte growth factor
HER3Human epidermal growth factor receptor 3
IHCImmunohistochemistry
ILDInterstitial lung disease
INK4bInhibitor of CDK4 (p15INK4b)
JNKc-Jun N-terminal kinase
Lgl2Lethal giant larvae homolog 2
LVEFLeft ventricular ejection fraction
MAPKMitogen-activated protein kinase
MDSMyelodysplastic syndromes
MEKMitogen-activated protein kinase kinase
METMesenchymal–epithelial transition/MET receptor tyrosine kinase
miR/miRNAMicroRNA
MMMalignant Mesothelioma
MMP/MMPsMatrix metalloproteinase(s)
MPNsMyeloproliferative neoplasms
MRONJMedication-related osteonecrosis of the jaw
mRNAMessenger RNA
mTORMechanistic target of rapamycin
NF-κBNuclear factor kappa-light-chain-enhancer of activated B cells
NSCLCNon-small cell lung cancer
ORRObjective response rate
PAK1p21-activated kinase 1
PATJPALS1-associated tight junction protein
PCPancreatic cancer
PCaProstate cancer
PDACPancreatic ductal adenocarcinoma
PDGFRPlatelet-derived growth factor receptor
PFSProgression-free survival
PI3KPhosphatidylinositol 3-kinase
PLCγPhospholipase C gamma
PTENPhosphatase and tensin homolog
QTcthe corrected QT interval
RAC1Ras-related C3 botulinum toxin substrate 1
RAFRapidly accelerated fibrosarcoma kinase
RASRat sarcoma virus oncogene
RCRectal cancer
RHORas homologous GTPase
RNARibonucleic acid
RONRecepteur d’origine nantais (RON receptor tyrosine kinase)
RTK(s)Receptor tyrosine kinase(s)
SHCSHC-transforming protein
SHP2Src homology region 2-containing protein tyrosine phosphatase 2 (PTPN11)
SLUGSnail family transcriptional repressor 2
SNAIL/SNAIL1/2Zinc finger transcription factors repressing E-cadherin
SMADTranscriptional mediators of TGF-β receptor signaling
SOSSon of Sevenless (guanine nucleotide exchange factor)
SRCProto-oncogene tyrosine-protein kinase Src
STAT/STAT3Signal transducer and activator of transcription
STK11Serine/threonine kinase 11
TAMTYRO3, AXL, MER receptor tyrosine kinase family
TGF-β(R)/(RI)Transforming growth factor-beta (receptor/receptor I)
TKITyrosine kinase inhibitor
TNF-αTumor necrosis factor-alpha
TP53Tumor protein p53
TregsRegulatory T cells
TWIST/TWIST1/2EMT-inducing transcription factors
VEGF(R)Vascular endothelial growth factor (receptor)
ZEB1/2Zinc finger E-box-binding homeobox 1/2
ZO-1Zonula occludens-1

References

  1. Chaffer, C.L.; Weinberg, R.A. A perspective on cancer cell metastasis. Science 2011, 331, 1559–1564. [Google Scholar] [CrossRef]
  2. Valastyan, S.; Weinberg, R.A. Tumor metastasis: Molecular insights and evolving paradigms. Cell 2011, 147, 275–292. [Google Scholar] [CrossRef]
  3. Nieto, M.A.; Huang, R.Y.; Jackson, R.A.; Thiery, J.P. EMT: 2016. Cell 2016, 166, 21–45. [Google Scholar] [CrossRef] [PubMed]
  4. Dongre, A.; Weinberg, R.A. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 69–84. [Google Scholar] [CrossRef]
  5. Jolly, M.K.; Ware, K.E.; Gilja, S.; Somarelli, J.A.; Levine, H. EMT and MET: Necessary or permissive for metastasis? Mol. Oncol. 2017, 11, 755–769. [Google Scholar] [CrossRef]
  6. Huang, Y.; Hong, W.; Wei, X. The Molecular Mechanisms and Therapeutic Strategies of EMT in Tumor Progression and Metastasis. J. Hematol. Oncol. 2022, 15, 129. [Google Scholar] [CrossRef]
  7. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [Google Scholar] [CrossRef]
  8. Bangarh, R.; Saini, R.V.; Saini, A.K.; Singh, T.; Joshi, H.; Ramniwas, S.; Shahwan, M.; Tuli, H.S. Dynamics of epithelial-mesenchymal plasticity driving cancer drug resistance. Cancer Pathog. Ther. 2024, 3, 120–128. [Google Scholar] [CrossRef] [PubMed]
  9. Sahoo, S.; Hari, K.; Jolly, M.K. Design principles of regulatory networks underlying epithelial mesenchymal plasticity in cancer cells. Curr. Opin. Cell Biol. 2025, 92, 102445. [Google Scholar] [CrossRef]
  10. Tsai, J.H.; Yang, J. Epithelial–mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013, 27, 2192–2206. [Google Scholar] [CrossRef] [PubMed]
  11. Ocaña, O.H.; Córcoles, R.; Fabra, A.; Moreno-Bueno, G.; Acloque, H.; Vega, S.; Barrallo-Gimeno, A.; Cano, A.; Nieto, M.A. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell 2012, 22, 709–724. [Google Scholar] [CrossRef]
  12. Yang, J.; Du, X.; Wang, G.; Sun, Y.; Chen, K.; Zhu, X.; Lazar, A.J.; Hunt, K.K.; Pollock, R.E.; Zhang, W. Mesenchymal to epithelial transition in sarcomas. Eur. J. Cancer 2014, 50, 593–601. [Google Scholar] [CrossRef]
  13. Tsai, J.H.; Donaher, J.L.; Murphy, D.A.; Chau, S.; Yang, J. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012, 22, 725–736. [Google Scholar] [CrossRef]
  14. Lou, Y.; Diao, L.; Cuentas, E.R.; Denning, W.L.; Chen, L.; Fan, Y.H.; Byers, L.A.; Wang, J.; Papadimitrakopoulou, V.A.; Behrens, C.; et al. Epithelial-Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma. Clin. Cancer Res. 2016, 22, 3630–3642. [Google Scholar] [CrossRef]
  15. Ye, X.; Weinberg, R.A. Epithelial–mesenchymal plasticity: A central regulator of cancer progression. Trends Cell Biol. 2015, 25, 675–686. [Google Scholar] [CrossRef] [PubMed]
  16. Gaponova, A.V.; Rodin, S.; Mazina, A.A.; Volchkov, P.V. Epithelial-Mesenchymal Transition: Role in Cancer Progression and the Perspectives of Antitumor Treatment. Acta Naturae 2020, 12, 4–23. [Google Scholar] [CrossRef] [PubMed]
  17. Zhang, Y.; Weinberg, R.A. Epithelial-to-mesenchymal transition in cancer: Complexity and opportunities. Front. Med. 2018, 12, 361–373. [Google Scholar] [CrossRef]
  18. Heldin, C.H.; Moustakas, A. Role of Smads in TGFβ signaling. Cell Tissue Res. 2012, 347, 21–36. [Google Scholar] [CrossRef] [PubMed]
  19. Trusolino, L.; Bertotti, A.; Comoglio, P.M. MET signalling: Principles and functions in development, organ regeneration and cancer. Nat. Rev. Mol. Cell Biol. 2010, 11, 834–848. [Google Scholar] [CrossRef]
  20. Meyer, A.S.; Miller, M.A.; Gertler, F.B.; Lauffenburger, D.A. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Sci. Signal. 2013, 6, ra66. [Google Scholar] [CrossRef]
  21. Goyette, M.A.; Côté, J.F. AXL Receptor Tyrosine Kinase as a Promising Therapeutic Target Directing Multiple Aspects of Cancer Progression and Metastasis. Cancers 2022, 14, 466. [Google Scholar] [CrossRef]
  22. Shibue, T.; Weinberg, R.A. EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 2017, 14, 611–629. [Google Scholar] [CrossRef]
  23. Herbertz, S.; Sawyer, J.S.; Stauber, A.J.; Gueorguieva, I.; Driscoll, K.E.; Estrem, S.T.; Cleverly, A.L.; Desaiah, D.; Guba, S.C.; Benhadji, K.A.; et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des. Devel. Ther. 2015, 9, 4479–4499. [Google Scholar] [CrossRef] [PubMed]
  24. Wolf, J.; Seto, T.; Han, J.Y.; Reguart, N.; Garon, E.B.; Groen, H.J.M.; Tan, D.S.; Hida, T.; De Jonge, M.J.; Orlov, S.; et al. Capmatinib in MET exon 14–mutated or MET-amplified non–small-cell lung cancer. N. Engl. J. Med. 2020, 383, 944–957. [Google Scholar] [CrossRef] [PubMed]
  25. Yadav, M.; Sharma, A.; Patne, K.; Tabasum, S.; Suryavanshi, J.; Rawat, L.; Machaalani, M.; Eid, M.; Singh, R.P.; Choueiri, T.K.; et al. AXL Signaling in Cancer: From Molecular Insights to Targeted Therapies. Signal Transduct. Target. Ther. 2025, 10, 37. [Google Scholar] [CrossRef] [PubMed]
  26. Zhou, W.; Fong, M.Y.; Min, Y.; Somlo, G.; Liu, L.; Palomares, M.R.; Yu, Y.; Chow, A.; O’Connor, S.T.; Chin, A.R.; et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 2014, 25, 501–515. [Google Scholar] [CrossRef]
  27. Singh, A.; Settleman, J. EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene 2010, 29, 4741–4751. [Google Scholar] [CrossRef]
  28. Du, B.; Shim, J.S. Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules 2016, 21, 965. [Google Scholar] [CrossRef]
  29. Tzavlaki, K.; Moustakas, A. TGF-β Signaling. Biomolecules 2020, 10, 487. [Google Scholar] [CrossRef]
  30. Sattler, M.; Salgia, R. The Expanding Role of the Receptor Tyrosine Kinase MET as a Therapeutic Target in Non-Small Cell Lung Cancer. Cell Rep. Med. 2025, 6, 101983. [Google Scholar] [CrossRef]
  31. Comoglio, P.M.; Giordano, S.; Trusolino, L. Drug development of MET inhibitors: Targeting oncogene addiction and expedience. Nat. Rev. Drug Discov. 2008, 7, 504–516. [Google Scholar] [CrossRef]
  32. Organ, S.L.; Tsao, M.S. An overview of the c-MET signaling pathway. Ther. Adv. Med. Oncol. 2011, 3 (Suppl. S1), S7–S19. [Google Scholar] [CrossRef]
  33. Satelli, A.; Li, S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell. Mol. Life Sci. 2011, 68, 3033–3046. [Google Scholar] [CrossRef]
  34. Wang, Y.; Shi, J.; Chai, K.; Ying, X.; Zhou, B.P. The Role of Snail in EMT and Tumorigenesis. Curr. Cancer Drug Targets 2013, 13, 963–972. [Google Scholar] [CrossRef]
  35. Wood, G.E.; Hockings, H.; Hilton, D.M.; Kermorgant, S. The Role of MET in Chemotherapy Resistance. Oncogene 2021, 40, 1927–1941. [Google Scholar] [CrossRef]
  36. Rai, G.P.; Shanker, A. The Coevolutionary Landscape of Drug Resistance in Epidermal Growth Factor Receptor: A Cancer Perspective. Comput. Biol. Med. 2025, 189, 110001. [Google Scholar] [CrossRef]
  37. Fischer, K.R.; Durrans, A.; Lee, S.; Sheng, J.; Li, F.; Wong, S.T.; Choi, H.; El Rayes, T.; Ryu, S.; Troeger, J.; et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015, 527, 472–476. [Google Scholar] [CrossRef] [PubMed]
  38. Zheng, X.; Carstens, J.L.; Kim, J.; Scheible, M.; Kaye, J.; Sugimoto, H.; Wu, C.C.; LeBleu, V.S.; Kalluri, R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015, 527, 525–530. [Google Scholar] [CrossRef] [PubMed]
  39. Akhurst, R.J.; Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov. 2012, 11, 790–811. [Google Scholar] [CrossRef]
  40. Massagué, J. TGFbeta in cancer. Cell 2008, 134, 215–230. [Google Scholar] [CrossRef] [PubMed]
  41. Melisi, D.; Garcia-Carbonero, R.; Macarulla, T.; Pezet, D.; Deplanque, G.; Fuchs, M.; Trojan, J.; Oettle, H.; Kozloff, M.; Cleverly, A.; et al. Galunisertib plus Gemcitabine vs. Gemcitabine for First-Line Treatment of Patients with Unresectable Pancreatic Cancer. Br. J. Cancer 2018, 119, 1208–1214. [Google Scholar] [CrossRef]
  42. Mariathasan, S.; Turley, S.J.; Nickles, D.; Castiglioni, A.; Yuen, K.; Wang, Y.; Kadel, E.E., III; Koeppen, H.; Astarita, J.L.; Cubas, R.; et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018, 554, 544–548. [Google Scholar] [CrossRef] [PubMed]
  43. Travis, M.A.; Sheppard, D. TGF-β activation and function in immunity. Annu. Rev. Immunol. 2014, 32, 51–82. [Google Scholar] [CrossRef] [PubMed]
  44. Christensen, J.G.; Burrows, J.; Salgia, R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005, 225, 1–26. [Google Scholar] [CrossRef]
  45. Mo, H.N.; Liu, P. Targeting MET in Cancer Therapy. Chronic Dis. Transl. Med. 2017, 3, 148–153. [Google Scholar] [CrossRef]
  46. Peng, W.T.; Sun, W.Y.; Li, X.R.; Sun, J.C.; Du, J.J.; Wei, W. Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2018, 19, 1366. [Google Scholar] [CrossRef]
  47. Engelsen, A.S.T.; Lotsberg, M.L.; Abou Khouzam, R.; Thiery, J.P.; Lorens, J.B.; Chouaib, S.; Terry, S. Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition. Front. Immunol. 2022, 13, 869676. [Google Scholar] [CrossRef]
  48. Shen, Y.; Chen, X.; He, J.; Liao, D.; Zu, X. Axl Inhibitors as Novel Cancer Therapeutic Agents. Life Sci. 2018, 198, 99–111. [Google Scholar] [CrossRef]
  49. Ou, X.; Gao, G.; Habaz, I.A.; Wang, Y. Mechanisms of Resistance to Tyrosine Kinase Inhibitor-Targeted Therapy and Overcoming Strategies. MedComm 2024, 5, e694. [Google Scholar] [CrossRef]
  50. Gjerdrum, C.; Tiron, C.; Høiby, T.; Stefansson, I.; Haugen, H.; Sandal, T.; Collett, K.; Li, S.; McCormack, E.; Gjertsen, B.T.; et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc. Natl. Acad. Sci. USA 2010, 107, 1124–1129. [Google Scholar] [CrossRef] [PubMed]
  51. Zhu, C.; Wei, Y.; Wei, X. AXL Receptor Tyrosine Kinase as a Promising Anti-Cancer Approach: Functions, Molecular Mechanisms and Clinical Applications. Mol. Cancer 2019, 18, 153. [Google Scholar] [CrossRef]
  52. Xu, Y.; Huang, Z.; Gong, L.; Fan, Y. A Case of Resistance to Tyrosine Kinase Inhibitor Therapy: Small Cell Carcinoma Transformation Concomitant with Plasma-Genotyped T790M Positivity. Anticancer Drugs 2017, 28, 1056–1061. [Google Scholar] [CrossRef]
  53. Allgayer, H.; Mahapatra, S.; Mishra, B.; Swain, B.; Saha, S.; Khanra, S.; Kumari, K.; Panda, V.K.; Malhotra, D.; Patil, N.S.; et al. Epithelial-to-Mesenchymal Transition (EMT) and Cancer Metastasis: The Status Quo of Methods and Experimental Models 2025. Mol. Cancer 2025, 24, 167. [Google Scholar] [CrossRef]
  54. Guarino, M. Epithelial–mesenchymal transition and tumour invasion. Int. J. Biochem. Cell Biol. 2007, 39, 2153–2160. [Google Scholar] [CrossRef] [PubMed]
  55. Fuxe, J.; Vincent, T.; Garcia de Herreros, A. Transcriptional crosstalk between TGF-β and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes. Cell Cycle 2010, 9, 2363–2374. [Google Scholar] [CrossRef] [PubMed]
  56. Thiery, J.P. Epithelial–mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2, 442–454. [Google Scholar] [CrossRef]
  57. Kalluri, R. EMT: When epithelial cells decide to become mesenchymal-like cells. J. Clin. Investig. 2009, 119, 1417–1419. [Google Scholar] [CrossRef] [PubMed]
  58. Zhang, J.; Tian, X.J.; Zhang, H.; Teng, Y.; Li, R.; Bai, F.; Elankumaran, S.; Xing, J. TGF-β–induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci. Signal. 2014, 7, ra91. [Google Scholar] [CrossRef]
  59. Moustakas, A.; Heldin, C.H. Mechanisms of TGFβ-induced epithelial–mesenchymal transition. J. Clin. Med. 2016, 5, 63. [Google Scholar] [CrossRef]
  60. Nieto, M.A. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu. Rev. Cell Dev. Biol. 2011, 27, 347–376. [Google Scholar] [CrossRef]
  61. Miyazawa, K.; Miyazono, K. Regulation of TGF-β Family Signaling by Inhibitory Smads. Cold Spring Harb. Perspect. Biol. 2017, 9, a022095. [Google Scholar] [CrossRef] [PubMed]
  62. Kowanetz, M.; Valcourt, U.; Bergström, R.; Heldin, C.H.; Moustakas, A. Id2 and Id3 Define the Potency of Cell Proliferation and Differentiation Responses to Transforming Growth Factor Beta and Bone Morphogenetic Protein. Mol. Cell. Biol. 2004, 24, 4241–4254. [Google Scholar] [CrossRef]
  63. Hao, Y.; Baker, D.; Ten Dijke, P. TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis. Int. J. Mol. Sci. 2019, 20, 2767. [Google Scholar] [CrossRef]
  64. Thiery, J.P.; Sleeman, J.P. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 2006, 7, 131–142. [Google Scholar] [CrossRef]
  65. Pastushenko, I.; Blanpain, C. EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol. 2019, 29, 212–226. [Google Scholar] [CrossRef]
  66. Biddle, A.; Gammon, L.; Liang, X.; Costea, D.E.; Mackenzie, I.C. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. EBioMedicine 2016, 4, 138–145. [Google Scholar] [CrossRef]
  67. Huang, R.Y.; Wong, M.K.; Tan, T.Z.; Kuay, K.T.; Ng, A.H.; Chung, V.Y.; Chu, Y.S.; Matsumura, N.; Lai, H.C.; Lee, Y.F.; et al. An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis. 2013, 4, e915. [Google Scholar] [CrossRef] [PubMed]
  68. Cheung, K.J.; Ewald, A.J. A collective route to metastasis: Seeding by tumor cell clusters. Science 2016, 352, 167–169. [Google Scholar] [CrossRef] [PubMed]
  69. Jolly, M.K.; Somarelli, J.A.; Sheth, M.; Biddle, A.; Tripathi, S.C.; Armstrong, A.J.; Hanash, S.M.; Bapat, S.A.; Rangarajan, A.; Levine, H. Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas. Pharmacol. Ther. 2019, 194, 161–184. [Google Scholar] [CrossRef]
  70. Aquino, A.; Franzese, O. Reciprocal modulation of tumour and immune cell motility: Uncovering dynamic interplays and therapeutic approaches. Cancers 2025, 17, 1547. [Google Scholar] [CrossRef]
  71. Bahcall, M.; Sim, T.; Paweletz, C.; Patel, J.D.; Sholl, L.M.; Sacher, A.G.; Lydon, C.; Kirschmeier, P.; Lawrence, M.S.; Awad, M.M.; et al. Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer. Cancer Discov. 2016, 6, 1334–1341. [Google Scholar] [CrossRef]
  72. Reungwetwattana, T.; Liang, Y.; Zhu, V.; Ou, S.H.I. The Race to Target MET Exon 14 Skipping Alterations in Non-Small Cell Lung Cancer: The Why, the How, the Who, the Unknown, and the Inevitable. Lung Cancer 2017, 103, 27–37. [Google Scholar] [CrossRef]
  73. Feng, H.; Xia, Y.; Wang, W.; Xu, C.; Wang, Q.; Song, Z.; Li, Z.; Yu, J.; Zhong, W.; Wang, Z.; et al. Expert consensus on the diagnosis and treatment of non-small cell lung cancer with MET alteration. Cancer Biol. Med. 2025, 22, 237–265. [Google Scholar] [CrossRef]
  74. Oksen, D.; Boutmy, E.; Wang, Y.; Stroh, C.; Johne, A.; Nisbett, A.R.; Ryder, A. Patients with advanced non-small cell lung cancer harboring MET alterations: A descriptive cohort study. Clin. Lung Cancer 2025, 26, e259–e269.e5. [Google Scholar] [CrossRef] [PubMed]
  75. Li, M.; Huang, J.; Xing, R.; Du, X.; Wei, C.; Wang, H. Exploring practical experience with different treatments in NSCLC patients with MET-deregulated: A retrospective analysis from the real world. BMC Pulm. Med. 2025, 25, 35. [Google Scholar] [CrossRef]
  76. Shek, R.C.M.; Li, P.S.N.; Leung, S.C.M.; Chu, H.T.; Hioe, F.; Tang, V.W.L.; Lui, Y.H.; Lam, L.R.S.; Ng, J.H.Y.; Wong, R.T.S.; et al. A novel digital PCR assay for accurate detection and differentiation of focal and non-focal subtypes of mesenchymal-epithelial transition (MET) gene amplification in lung cancer. Cancers 2025, 17, 811. [Google Scholar] [CrossRef] [PubMed]
  77. Chen, T.; Liu, G.; Chen, S.; Zhang, F.; Ma, S.; Bai, Y.; Zhang, Q.; Ding, Y. Natural product mediated mesenchymal-epithelial remodeling by covalently binding ENO1 to degrade m6A modified β-catenin mRNA. Acta Pharm. Sin. B 2025, 15, 467–483. [Google Scholar] [CrossRef]
  78. Xu, Y.; Chen, Y.; Zhang, J.; Wang, J.; Yang, S.; Zhao, H.; Wu, L.; Lei, J.; Zhou, Y.; Peng, J.; et al. RNASET2 deficiency induces hepatocellular carcinoma metastasis through cholesterol-triggered MET activation. Adv. Sci. 2025, 12, e2411888. [Google Scholar] [CrossRef]
  79. Miglio, U.; Berrino, E.; Avanzato, D.; Molineris, I.; Miano, V.; Milan, M.; Lanzetti, L.; Morelli, E.; Hughes, J.M.; De Bortoli, M.; et al. Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells. Mol. Ther. Nucleic Acids 2025, 36, 102529. [Google Scholar] [CrossRef] [PubMed]
  80. Xia, Y.; Huang, C.; Zhong, M.; Zhong, H.; Ruan, R.; Xiong, J.; Yao, Y.; Zhou, J.; Deng, J. Targeting HGF/c-MET signaling to regulate the tumor microenvironment: Implications for counteracting tumor immune evasion. Cell Commun. Signal. 2025, 23, 46. [Google Scholar] [CrossRef]
  81. Ma, P.C.; Tretiakova, M.S.; MacKinnon, A.C.; Ramnath, N.; Johnson, C.; Dietrich, S.; Maulik, G.; Christensen, J.G.; Salgia, R. Expression and Mutational Analysis of MET in Human Solid Cancers. Genes Chromosomes Cancer 2008, 47, 1025–1037. [Google Scholar] [CrossRef]
  82. Vansteenkiste, J.F.; Van De Kerkhove, C.; Wauters, E.; Van Mol, P. Capmatinib for the Treatment of Non-Small Cell Lung Cancer. Expert Rev. Anticancer Ther. 2019, 19, 659–671. [Google Scholar] [CrossRef]
  83. Kron, A.; Scheffler, M.; Wiesweg, M.; Hummel, H.D.; Kulhavy, J.; Gatteloehner, S.; Kollmeier, J.; Schubart, C.; Groß, T.; Demes, M.C.; et al. Indirect Comparison of Capmatinib Treatment from GEOMETRY Mono-1 Trial to SOC in German Patients with Locally Advanced or Metastatic NSCLC Harboring METex14 Skipping Mutations. Eur. J. Cancer 2024, 207, 114158. [Google Scholar] [CrossRef]
  84. Roskoski, R., Jr. Targeted and Cytotoxic Inhibitors Used in the Treatment of Lung Cancers. Pharmacol. Res. 2024, 209, 107465. [Google Scholar] [CrossRef]
  85. Rothenberger, N.J.; Stabile, L.P. Hepatocyte Growth Factor/c-Met Signaling in Head and Neck Cancer and Implications for Treatment. Cancers 2017, 9, 39. [Google Scholar] [CrossRef] [PubMed]
  86. Rivas, S.; Sepúlveda, R.V.; Tapia, I.; Estay, C.; Soto, V.; Blanco, A.; González, E.; Armisen, R. MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients. Int. J. Mol. Sci. 2024, 25, 13715. [Google Scholar] [CrossRef] [PubMed]
  87. Tanaka, T.; Makimoto, G.; Sumii, R.; Omote, R.; Ando, Y.; Ninomiya, K.; Ichihara, E.; Ohashi, K.; Maeda, Y.; Tabata, M. Remarkable Efficacy of Capmatinib in a Patient with Cancer of Unknown Primary with MET Amplification: A Case Report. Intern. Med. 2025, (Online ahead of print). 1–5. [Google Scholar] [CrossRef] [PubMed]
  88. Akioka, T.; Kimura, S.; Katayama, Y.; Fujii, M.; Kiwaki, T.; Kawaguchi, M.; Fukushima, T.; Sato, Y.; Mukai, S.; Kamoto, T.; et al. Phosphorylation of MET Is Upregulated in Metastatic Sites of Renal Cell Carcinoma: Possible Role of MET and Hepatocyte Growth Factor Activation-Targeted Combined Therapy. Biomedicines 2025, 13, 811. [Google Scholar] [CrossRef]
  89. Bladt, F.; Friese-Hamim, M.; Ihling, C.; Wilm, C.; Blaukat, A. The c-Met Inhibitor MSC2156119J Effectively Inhibits Tumor Growth in Liver Cancer Models. Cancers 2014, 6, 1736–1752. [Google Scholar] [CrossRef]
  90. Mallareddy, J.R.; Yang, L.; Lin, W.H.; Feathers, R.; Ayers-Ringler, J.; Tolosa, E.; Kizhake, A.G.; Kizhake, S.; Kubica, S.P.; Boghean, L.; et al. Fluorescence Based Live Cell Imaging Identifies Exon 14 Skipped Hepatocyte Growth Factor Receptor (MET) Degraders. RSC Adv. 2025, 15, 10419–10425. [Google Scholar] [CrossRef]
  91. Liu, Z.; Liu, W.; Shen, X.; Jiang, T.; Li, X.; Liu, H.; Zheng, Z. Molecular Mechanism of Type Ib MET Inhibitors and Their Potential for CNS Tumors. Sci. Rep. 2025, 15, 6926. [Google Scholar] [CrossRef]
  92. Wolf, J.; Hochmair, M.; Han, J.Y.; Reguart, N.; Souquet, P.J.; Smit, E.F.; Orlov, S.V.; Vansteenkiste, J.; Nishio, M.; de Jonge, M.; et al. Capmatinib in MET Exon 14-Mutated Non-Small-Cell Lung Cancer: Final Results from the Open-Label, Phase 2 GEOMETRY Mono-1 Trial. Lancet Oncol. 2024, 25, 1357–1370. [Google Scholar] [CrossRef] [PubMed]
  93. Reale, M.L.; Passiglia, F.; Cappuzzo, F.; Minuti, G.; Occhipinti, M.; Bulotta, A.; Delmonte, A.; Sini, C.; Galetta, D.; Roca, E.; et al. MET Exon 14 Skipping Mutations in Non-Small-Cell Lung Cancer: Real-World Data from the Italian Biomarker ATLAS Database. ESMO Open 2024, 9, 103680. [Google Scholar] [CrossRef]
  94. Novartis, A.G. Novartis Investigational Lung Cancer Therapy Capmatinib (INC280) Granted FDA Breakthrough Therapy Designation for Patients with MET-Mutated Advanced Non-Small Cell Lung Cancer. Available online: https://www.novartis.com/news/media-releases/novartis-investigational-lung-cancer-therapy-capmatinib-inc280-granted-fda-breakthrough-therapy-designation-patients-met-mutated-advanced-non-small-cell-lung-cancer (accessed on 9 June 2025).
  95. Schuler, M.; Berardi, R.; Lim, W.T.; de Jonge, M.; Bauer, T.M.; Azaro, A.; Gottfried, M.; Han, J.Y.; Lee, D.H.; Wollner, M.; et al. Molecular Correlates of Response to Capmatinib in Advanced Non-Small-Cell Lung Cancer: Clinical and Biomarker Results from a Phase I Trial. Ann. Oncol. 2020, 31, 789–797. [Google Scholar] [CrossRef]
  96. Drilon, A.; Cappuzzo, F.; Ou, S.H.I.; Camidge, D.R. Targeting MET in Lung Cancer: Will Expectations Finally Be MET? J. Thorac. Oncol. 2017, 12, 15–26. [Google Scholar] [CrossRef] [PubMed]
  97. Han, Y.; Yu, Y.; Miao, D.; Zhou, M.; Zhao, J.; Shao, Z.; Jin, R.; Le, X.; Li, W.; Xia, Y. Targeting MET in NSCLC: An Ever-Expanding Territory. JTO Clin. Res. Rep. 2024, 5, 100630. [Google Scholar] [CrossRef]
  98. Guo, X.J.; Cai, X.T.; Rong, Z.X.; Zhang, Y.P.; Wen, Y.X.; Bai, X.; Wang, J.; Fu, Q.J.; Guo, Z.Q.; Long, L.L.; et al. Interstitial Pneumonitis Associated with Combined Regimen of Immunotherapy and Conventional Therapies—Pharmacovigilance Database Analysis with Real-World Data Validation. BMC Med. 2023, 21, 6. [Google Scholar] [CrossRef]
  99. Weller, M.; Remon, J.; Rieken, S.; Vollmuth, P.; Ahn, M.J.; Minniti, G.; Le Rhun, E.; Westphal, M.; Brastianos, P.K.; Soo, R.A.; et al. Central Nervous System Metastases in Advanced Non-Small Cell Lung Cancer: A Review of the Therapeutic Landscape. Cancer Treat. Rev. 2024, 130, 102807. [Google Scholar] [CrossRef] [PubMed]
  100. Sisi, M.; Vitale, G.; Fusaroli, M.; Riefolo, M.; Giunchi, V.; D’Errico, A.; Ardizzoni, A.; Raschi, E.; Gelsomino, F. Capmatinib-Induced Liver Injury as Emerging Toxicity of MET Inhibitors in Patients with NSCLC Pretreated with Immune Checkpoint Inhibitors. JTO Clin. Res. Rep. 2023, 4, 100563. [Google Scholar] [CrossRef]
  101. Stanzione, B.; Del Conte, A.; Bertoli, E.; De Carlo, E.; Bortolot, M.; Torresan, S.; Spina, M.; Bearz, A. Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Common Mutations: New Strategies. Cancers 2025, 17, 1515. [Google Scholar] [CrossRef]
  102. Asiedu, M.K.; Beauchamp-Perez, F.D.; Ingle, J.N.; Behrens, M.D.; Radisky, D.C.; Knutson, K.L. AXL Induces Epithelial-to-Mesenchymal Transition and Regulates the Function of Breast Cancer Stem Cells. Oncogene 2014, 33, 1316–1324. [Google Scholar] [CrossRef]
  103. Aiello, N.M.; Maddipati, R.; Norgard, R.J.; Balli, D.; Li, J.; Yuan, S.; Yamazoe, T.; Black, T.; Sahmoud, A.; Furth, E.E.; et al. EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration. Dev. Cell 2018, 45, 681–695.e4. [Google Scholar] [CrossRef]
  104. Dagogo-Jack, I.; Moonsamy, P.; Gainor, J.F.; Lennerz, J.K.; Piotrowska, Z.; Lin, J.J.; Lennes, I.T.; Sequist, L.V.; Shaw, A.T.; Goodwin, K.; et al. A Phase 2 Study of Capmatinib in Patients with MET-Altered Lung Cancer Previously Treated with a MET Inhibitor. J. Thorac. Oncol. 2021, 16, 850–859. [Google Scholar] [CrossRef]
  105. Cui, X.; Chen, X.; Pognan, N.; Sengupta, T.; Rahmanzadeh, G.; Kornberger, R.; Giovannini, M. Evaluation of the Pharmacokinetic Drug Interaction of Capmatinib with Itraconazole and Rifampicin and Potential Impact on Renal Transporters in Healthy Subjects. J. Clin. Pharmacol. 2023, 63, 228–238. [Google Scholar] [CrossRef] [PubMed]
  106. U.S. Food and Drug Administration. FDA Approves Capmatinib for Metastatic Non-Small Cell Lung Cancer. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capmatinib-metastatic-non-small-cell-lung-cancer (accessed on 9 June 2025).
  107. Capmatinib. Tabrecta. Eropean Medicines Agency. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/tabrecta (accessed on 5 June 2025).
  108. Wu, Y.L.; Smit, E.F.; Bauer, T.M. Capmatinib for Patients with Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutations: A Review of Preclinical and Clinical Studies. Cancer Treat. Rev. 2021, 95, 102173. [Google Scholar] [CrossRef] [PubMed]
  109. Reyes, A.; Muddasani, R.; Massarelli, E. Overcoming resistance to checkpoint inhibitors with combination strategies in the treatment of non-small cell lung cancer. Cancers 2024, 16, 2919. [Google Scholar] [CrossRef]
  110. Hu, D.; Hu, Y.; Lei, S.; Wu, D.; Wang, Y. MET Tyrosine Kinase Inhibitors in Combination with EGFR Tyrosine Kinase Inhibitors in NSCLC Patients with EGFR Mutations and Acquired MET Alterations: A Systematic Review and Meta-Analysis. BMC Cancer 2025, 25, 732. [Google Scholar] [CrossRef] [PubMed]
  111. Lara, M.S.; Riess, J.W.; Goldman, J.W.; Jiang, F.; Bivona, T.G.; Blakely, C.M. Current Trial Report: A Multicenter Phase I/Ib Study of Capmatinib Plus Trametinib in Patients with Metastatic Nonsmall Cell Lung Center Harboring MET Exon 14 Skipping Mutations and Other MET-Alterations. Clin. Lung Cancer 2024, 25, 732–737. [Google Scholar] [CrossRef]
  112. Cortot, A.; Le, X.; Smit, E.; Viteri, S.; Kato, T.; Sakai, H.; Park, K.; Camidge, D.R.; Berghoff, K.; Vlassak, S.; et al. Safety of MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14 Skipping Non-Small Cell Lung Cancer: A Clinical Review. Clin. Lung Cancer 2022, 23, 195–207. [Google Scholar] [CrossRef]
  113. DeAzevedo, R.; Steiner, M.; Turner, B.X.; Liu, A.; Newton, S.; Schmidt, J.; Fleming, R.; Tolentino, A.; Kaseb, A.O.; Curran, M.A. Type I MET Inhibitors Cooperate with PD-1 Blockade to Promote Rejection of Hepatocellular Carcinoma. J. Immunother. Cancer 2024, 12, e009690. [Google Scholar] [CrossRef]
  114. Carouge, E.; Burnichon, C.; Figeac, M.; Sebda, S.; Vanpouille, N.; Vinchent, A.; Truong, M.J.; Duterque-Coquillaud, M.; Tulasne, D.; Chotteau-Lelièvre, A. Functional Interaction between Receptor Tyrosine Kinase MET and ETS Transcription Factors Promotes Prostate Cancer Progression. Mol. Oncol. 2025, 19, 474–495. [Google Scholar] [CrossRef]
  115. Ueta, A.; Yamada, A.; Yoshioka, M.; Kanai, M.; Muto, M.; Okita, N. Remarkable Response to Capmatinib in a Patient with Intrahepatic Cholangiocarcinoma Harboring TFG-MET Fusion. Int. Cancer Conf. J. 2024, 13, 199–203. [Google Scholar] [CrossRef]
  116. Alves de Souza, G.; Dornellas, D.M.S.; Campregher, P.V.; Teixeira, C.H.A.; Schvartsman, G. Complete Response to Capmatinib in a Patient with Metastatic Lung Adenocarcinoma Harboring CD47-MET Fusion: A Case Report. Oncologist 2024, 29, 764–767. [Google Scholar] [CrossRef]
  117. Falchook, G.S.; Battiste, J.D.; Kalra, A.; Shastry, M.; Finney, L.; Hoekstra, S.J.; Shih, M.G.; Shih, K.C. A Phase Ib Study Evaluating the c-MET Inhibitor INC280 (Capmatinib) in Combination with Bevacizumab in Patients with High-Grade Glioma. Neurooncol. Adv. 2024, 7, vdae220. [Google Scholar] [CrossRef]
  118. Batra, U.; Singh, A.K.; Nathany, S.; Dewan, A.; Sharma, M.; Amrith, B.P.; Mehta, A.; Batra, V.; Noronha, V.; Prabhash, K. Real world experience with MET inhibitors in MET exon 14 skipping mutated non-small cell lung cancer: Largest Indian perspective. Discov. Oncol. 2025, 16, 286. [Google Scholar] [CrossRef]
  119. Solomon, B.J.; Mok, T.; Kim, D.W.; Wu, Y.L.; Nakagawa, K.; Mekhail, T.; Felip, E.; Cappuzzo, F.; Paolini, J.; Usari, T.; et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N. Engl. J. Med. 2014, 371, 2167–2177. [Google Scholar] [CrossRef]
  120. Feng, Y.; Ma, P.C. MET targeted therapy for lung cancer: Clinical development and future directions. Lung Cancer 2012, 3, 53–67. [Google Scholar] [CrossRef] [PubMed]
  121. Chen, S.H.; Yu, J.H.; Lin, Y.C.; Chang, Y.M.; Liu, N.T.; Chen, S.F. Application of an Integrated Single-Cell and Three-Dimensional Spheroid Culture Platform for Investigating Drug Resistance Heterogeneity and Epithelial-Mesenchymal Transition (EMT) in Lung Cancer Subclones. Int. J. Mol. Sci. 2025, 26, 1766. [Google Scholar] [CrossRef]
  122. Li, X.; Lu, Y.; Zhao, J.; Yu, Y.; Tian, H.; Zhu, H.; Li, W.; Xia, Y.; Chen, L. Savolitinib Conferred Sensitivity in a Patient with D1228H Mutation-Induced Capmatinib-Resistant MET Exon 14 Skipping Mutated Lung Adenocarcinoma. J. Cancer Res. Clin. Oncol. 2024, 150, 395. [Google Scholar] [CrossRef] [PubMed]
  123. Jóri, B.; Bundschuh, O.; Falk, M.; Heukamp, L.C.; Kluge, A.; Tiemann, M.; Willborn, K.C.; Woitzik, J.; Griesinger, F. Intracranial Response to Capmatinib after Progression on Crizotinib in a Patient with MET Exon 14 Skipping Non-Small Cell Lung Cancer—A Case Report. Transl. Lung Cancer Res. 2024, 13, 1749–1755. [Google Scholar] [CrossRef] [PubMed]
  124. Engelman, J.A.; Zejnullahu, K.; Mitsudomi, T.; Song, Y.; Hyland, C.; Park, J.O.; Lindeman, N.; Gale, C.M.; Zhao, X.; Christensen, J.; et al. MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling. Science 2007, 316, 1039–1043. [Google Scholar] [CrossRef]
  125. Bardelli, A.; Corso, S.; Bertotti, A.; Hobor, S.; Valtorta, E.; Siravegna, G.; Sartore-Bianchi, A.; Scala, E.; Cassingena, A.; Zecchin, D.; et al. Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer. Cancer Discov. 2013, 3, 658–673. [Google Scholar] [CrossRef]
  126. Lamouille, S.; Xu, J.; Derynck, R. Molecular Mechanisms of Epithelial-Mesenchymal Transition. Nat. Rev. Mol. Cell Biol. 2014, 15, 178–196. [Google Scholar] [CrossRef]
  127. Dagogo-Jack, I.; Shaw, A.T. Tumour Heterogeneity and Resistance to Cancer Therapies. Nat. Rev. Clin. Oncol. 2018, 15, 81–94. [Google Scholar] [CrossRef]
  128. Lai, Y.; Zhao, Z.; Zeng, T.; Liang, X.; Chen, D.; Duan, X.; Zeng, G.; Wu, W. Crosstalk between VEGFR and Other Receptor Tyrosine Kinases for TKI Therapy of Metastatic Renal Cell Carcinoma. Cancer Cell Int. 2018, 18, 31. [Google Scholar] [CrossRef]
  129. Tan, T.Z.; Miow, Q.H.; Miki, Y.; Noda, T.; Mori, S.; Huang, R.Y.; Thiery, J.P. Epithelial–Mesenchymal Transition Spectrum Quantification and Its Efficacy in Deciphering Survival and Drug Responses of Cancer Patients. EMBO Mol. Med. 2014, 6, 1279–1293. [Google Scholar] [CrossRef]
  130. Pastushenko, I.; Brisebarre, A.; Sifrim, A.; Fioramonti, M.; Revenco, T.; Boumahdi, S.; Van Keymeulen, A.; Brown, D.; Moers, V.; Lemaire, S.; et al. Identification of the Tumour Transition States Occurring during EMT. Nature 2018, 556, 463–468. [Google Scholar] [CrossRef] [PubMed]
  131. Jolly, M.K.; Boareto, M.; Debeb, B.G.; Aceto, N.; Farach-Carson, M.C.; Woodward, W.A.; Levine, H. Inflammatory Breast Cancer: A Model for Investigating Cluster-Based Dissemination. NPJ Breast Cancer 2017, 3, 21. [Google Scholar] [CrossRef]
  132. Cascetta, P.; Sforza, V.; Manzo, A.; Carillio, G.; Palumbo, G.; Esposito, G.; Montanino, A.; Costanzo, R.; Sandomenico, C.; De Cecio, R.; et al. RET Inhibitors in Non-Small-Cell Lung Cancer. Cancers 2021, 13, 4415. [Google Scholar] [CrossRef] [PubMed]
  133. Remon, J.; Hendriks, L.E.L.; Mountzios, G.; García-Campelo, R.; Saw, S.P.L.; Uprety, D.; Recondo, G.; Villacampa, G.; Reck, M. MET alterations in NSCLC—Current perspectives and future challenges. J. Thorac. Oncol. 2023, 18, 419–435. [Google Scholar] [CrossRef] [PubMed]
  134. Kang, J.; Deng, Q.M.; Feng, W.; Chen, Z.H.; Su, J.W.; Chen, H.J.; Wang, W.X.; Zhang, S.; Wang, Q.; Chen, Z.; et al. Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer. Lung Cancer 2023, 178, 66–74. [Google Scholar] [CrossRef]
  135. Jin, F.; Lin, Y.; Yuan, W.; Wu, S.; Yang, M.; Ding, S.; Liu, J.; Chen, Y. Recent advances in c-Met-based dual inhibitors in the treatment of cancers. Eur. J. Med. Chem. 2024, 272, 116477. [Google Scholar] [CrossRef] [PubMed]
  136. Chiang, Y.Y.; Chow, K.C.; Lin, T.Y.; Chiang, I.P.; Fang, H.Y. Hepatocyte growth factor and HER2/neu downregulate expression of apoptosis-inducing factor in non-small cell lung cancer. Oncol. Rep. 2014, 31, 597–604. [Google Scholar] [CrossRef]
  137. Sequist, L.V.; Waltman, B.A.; Dias-Santagata, D.; Digumarthy, S.; Turke, A.B.; Fidias, P.; Bergethon, K.; Shaw, A.T.; Gettinger, S.; Cosper, A.K.; et al. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Sci. Transl. Med. 2011, 3, 75ra26. [Google Scholar] [CrossRef]
  138. Kazandjian, D.; Blumenthal, G.M.; Chen, H.Y.; He, K.; Patel, M.; Justice, R.; Keegan, P.; Pazdur, R. FDA approval summary: Crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist 2014, 19, e5–e11. [Google Scholar] [CrossRef]
  139. Nosaki, K.; Yoh, K.; Toyozawa, R.; Horinouchi, H.; Morise, M.; Ohashi, K.; Murakami, H.; Satouchi, M.; Sakakibara-Konishi, J.; Yano, S.; et al. Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: A Co-MET study. Int. J. Clin. Oncol. 2024, 29, 1142–1151. [Google Scholar] [CrossRef]
  140. Soria, J.C.; Ohe, Y.; Vansteenkiste, J.; Reungwetwattana, T.; Chewaskulyong, B.; Lee, K.H.; Dechaphunkul, A.; Imamura, F.; Nogami, N.; Kurata, T.; et al. Osimertinib in Untreated EGFR-Mutated Advanced NSCLC. N. Engl. J. Med. 2018, 378, 113–125. [Google Scholar] [CrossRef] [PubMed]
  141. Owusu, B.Y.; Galemmo, R.; Janetka, J.; Klampfer, L. Hepatocyte Growth Factor, a Key Tumor-Promoting Factor in the Tumor Microenvironment. Cancers 2017, 9, 35. [Google Scholar] [CrossRef] [PubMed]
  142. Van Herpe, F.; Van Cutsem, E. The Role of cMET in Gastric Cancer-A Review of the Literature. Cancers 2023, 15, 1976. [Google Scholar] [CrossRef]
  143. Zhang, Z.; Lee, J.C.; Lin, L.; Olivas, V.; Au, V.; LaFramboise, T.; Abdel-Rahman, M.; Wang, X.; Levine, A.D.; Rho, J.K.; et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 2012, 44, 852–860. [Google Scholar] [CrossRef]
  144. Linger, R.M.; Keating, A.K.; Earp, H.S.; Graham, D.K. TAM receptor tyrosine kinases: Biological functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 2008, 100, 35–83. [Google Scholar] [CrossRef]
  145. Mamun, Y.; Chadni, S.H.; Rayala, R.; Ferdous, S.; Pokhrel, R.; Nefzi, A.; Chapagain, P.; Tse-Dinh, Y.C. Identification of Novel Human Topoisomerase III Beta Inhibitors. bioRxiv 2025, preprint. [Google Scholar] [CrossRef]
  146. Pirson, S.; Gautier-Isola, M.; Baudin, L.; Rouaud, L.; Vanwynsberghe, A.; Deroye, J.; Bekisz, S.; Gucciardo, F.; Lebeau, A.; Buntinx, F.; et al. AXL Promotes Lymphangiogenesis by Amplifying VEGF-C-Mediated AKT Pathway. Cell Mol. Life Sci. 2025, 82, 95. [Google Scholar] [CrossRef]
  147. Majumder, A.; Hosseinian, S.; Stroud, M.; Adhikari, E.; Saller, J.J.; Smith, M.A.; Zhang, G.; Agarwal, S.; Creixell, M.; Meyer, B.S.; et al. Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration. Mol. Cancer Res. 2022, 20, 542–555. [Google Scholar] [CrossRef] [PubMed]
  148. Holland, S.J.; Pan, A.; Franci, C.; Hu, Y.; Chang, B.; Li, W.; Duan, M.; Torneros, A.; Yu, J.; Heckrodt, T.; et al. R428, a selective small molecule inhibitor of AXL kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010, 70, 1544–1554. [Google Scholar] [CrossRef]
  149. Xu, J.; Lamouille, S.; Derynck, R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 2009, 19, 156–172. [Google Scholar] [CrossRef] [PubMed]
  150. Gay, C.M.; Balaji, K.; Byers, L.A. Giving AXL the axe: Targeting AXL in human malignancy. Br. J. Cancer 2017, 116, 415–423. [Google Scholar] [CrossRef]
  151. Wilson, C.; Ye, X.; Pham, T.; Lin, E.; Chan, S.; McNamara, E.; Neve, R.M.; Belmont, L.; Koeppen, H.; Yauch, R.L.; et al. AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs. Cancer Res. 2014, 74, 5878–5890. [Google Scholar] [CrossRef] [PubMed]
  152. Ben-Batalla, I.; Schultze, A.; Wroblewski, M.; Erdmann, R.; Heuser, M.; Waizenegger, J.S.; Riecken, K.; Binder, M.; Schewe, D.; Sawall, S.; et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood 2013, 122, 2443–2452. [Google Scholar] [CrossRef]
  153. Grøndal, S.M.; Blø, M.; Nilsson, L.I.H.; Rayford, A.J.; Jackson, A.; Gausdal, G.; Lorens, J.B. Targeting AXL Cellular Networks in Kidney Fibrosis. Front. Immunol. 2024, 15, 1446672. [Google Scholar] [CrossRef]
  154. Wu, S.; Liao, M.; Li, M.; Sun, M.; Xi, N.; Zeng, Y. Structure-based discovery of potent inhibitors of Axl: Design, synthesis, and biological evaluation. RSC Med. Chem. 2022, 13, 1246–1264. [Google Scholar] [CrossRef]
  155. Inoue, S.; Yamane, Y.; Tsukamoto, S.; Azuma, H.; Nagao, S.; Murai, N.; Nishibata, K.; Fukushima, S.; Ichikawa, K.; Nakagawa, T.; et al. Discovery of a potent and selective Axl inhibitor in preclinical model. Bioorg. Med. Chem. 2021, 39, 116137. [Google Scholar] [CrossRef] [PubMed]
  156. Kanlikilicer, P.; Ozpolat, B.; Aslan, B.; Bayraktar, R.; Gurbuz, N.; Rodriguez-Aguayo, C.; Bayraktar, E.; Denizli, M.; Gonzalez-Villasana, V.; Ivan, C.; et al. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models. Mol. Ther. Nucleic Acids 2017, 9, 251–262. [Google Scholar] [CrossRef]
  157. Byers, L.A.; Diao, L.; Wang, J.; Saintigny, P.; Girard, L.; Peyton, M.; Shen, L.; Fan, Y.; Giri, U.; Tumula, P.K.; et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies AXL as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 2013, 19, 279–290. [Google Scholar] [CrossRef]
  158. Liu, Y.; Xu, L.; Dou, Y.; He, Y. AXL: Shapers of Tumor Progression and Immunosuppressive Microenvironments. Mol. Cancer 2025, 24, 11. [Google Scholar] [CrossRef]
  159. Lv, Y.; Zhu, J.; Ge, S.; Jiang, T.; Xu, Y.; Yao, W.; Jiang, C. The AXL-mediated modulation of myeloid-derived suppressor cells (MDSC) in nasopharyngeal carcinoma. Med. Oncol. 2024, 42, 17. [Google Scholar] [CrossRef]
  160. Woo, S.M.; Min, K.J.; Seo, S.U.; Kim, S.; Kubatka, P.; Park, J.W.; Kwon, T.K. Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma. Int. J. Mol. Sci. 2019, 20, 3253. [Google Scholar] [CrossRef]
  161. Wu, Y.; Deng, J.; Rychahou, P.G.; Qiu, S.; Evers, B.M.; Zhou, B.P. Stabilization of Snail by NF-κB is required for inflammation-induced cell migration and invasion. Cancer Cell 2009, 15, 416–428. [Google Scholar] [CrossRef] [PubMed]
  162. Yim, J.; Hope, C.; Huelse, J.M.; Graham, D.K. Prospects of Current AXL-Targeting Therapies in Early Phase Cancer Trials. Expert Opin. Investig. Drugs 2025, in press. [Google Scholar] [CrossRef]
  163. Bhalla, S.; Gerber, D.E. AXL Inhibitors: Status of Clinical Development. Curr. Oncol. Rep. 2023, 25, 521–529. [Google Scholar] [CrossRef]
  164. Taniguchi, H.; Yamada, T.; Wang, R.; Tanimura, K.; Adachi, Y.; Nishiyama, A.; Tanimoto, A.; Takeuchi, S.; Araujo, L.H.; Boroni, M.; et al. AXL Confers Intrinsic Resistance to Osimertinib and Advances the Emergence of Tolerant Cells. Nat. Commun. 2019, 10, 259. [Google Scholar] [CrossRef] [PubMed]
  165. Sang, Y.B.; Kim, J.H.; Kim, C.G.; Hong, M.H.; Kim, H.R.; Cho, B.C.; Lim, S.M. The Development of AXL Inhibitors in Lung Cancer: Recent Progress and Challenges. Front. Oncol. 2022, 12, 811247. [Google Scholar] [CrossRef]
  166. Veluswamy, R.; Bhalla, S.; Mehra, R.; Garassino, M.C.; Gligich, O.; Oliva, C.; Gorcea-Carson, C.; McCracken, N.W. Phase 1b/2a Safety and Tolerability Study of Bemcentinib (BEM) with Pembrolizumab/Carboplatin/Pemetrexed in First Line (1L) Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Without/With a STK11 Mutation. J. Clin. Oncol. 2023, 41 (Suppl. S16), TPS9154. [Google Scholar] [CrossRef]
  167. Loges, S.; Heuser, M.; Chromik, J.; Sutamtewagul, G.; Kapp-Schwoerer, S.; Crugnola, M.; Di Renzo, N.; Lemoli, R.M.; Mattei, D.G.; Ben Batalla, I.; et al. Phase Ib/II Study (NCT02488408/BGBC003) of Bemcentinib Monotherapy or in Combination with Cytarabine or Decitabine in Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS): FINAL Results. Blood 2023, 142 (Suppl. S1), 4287. [Google Scholar] [CrossRef]
  168. Felip, E.; Brunsvig, P.; Vinolas, N.; Ponce Aix, S.; Carcereny Costa, E.; Dómine Gomez, M.; Trigo Perez, J.M.; Arriola, E.; Garcia Campelo, R.; Spicer, J.F.; et al. A phase II study of bemcentinib (BGB324), a first-in-class highly selective AXL inhibitor, with pembrolizumab in pts with advanced NSCLC: OS for stage I and preliminary stage II efficacy. J. Clin. Oncol. 2019, 37 (Suppl. S15), 9098. [Google Scholar] [CrossRef]
  169. Lorens, J.; Arce-Lara, C.E.; Arriola, E.; Brunsvig, P.; Carcereny Costa, E.; Domine, M.; Dragnev, K.H.; Felip, E.; Garcia Campelo, R.; Krebs, M.; et al. Phase II open-label, multi-centre study of bemcentinib (BGB324), a first-in-class selective AXL inhibitor, in combination with pembrolizumab in patients with advanced NSCLC. J. Clin. Oncol. 2018, 36 (Suppl. S15), 307. [Google Scholar] [CrossRef]
  170. Bhalla, S.; Fattah, F.J.; Williams, J.N.; Macchiaroli, A.; Padro, J.; Pogue, M.; Dowell, J.; Brekken, R.A.; Putnam, W.C.; McCracken, N.W.; et al. Phase 1 dose escalation and expansion study of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced NSCLC. J. Clin. Oncol. 2022, 40 (Suppl. S16). [Google Scholar] [CrossRef]
  171. Felip, E.; Krebs, M.G.; Carcereny, E.; Smeland, K.B.; Arriola, E.; Llacer Perez, C.; Thompson, J.; Paz-Ares, L.; Domine Gomez, M.; Olivares, J.R.; et al. 1440P Final top-line results of the BGBC008 phase II, multicenter study of bemcentinib and pembrolizumab (bem+pembro) in second-line (2L) advanced non-squamous (NS) non-small cell lung cancer (NSCLC) (NCT03184571). Ann. Oncol. 2023, 34, S819. [Google Scholar] [CrossRef]
  172. Vandewalle, N.; De Beule, N.; De Becker, A.; De Bruyne, E.; Menu, E.; Vanderkerken, K.; Breckpot, K.; Devoogdt, N.; De Veirman, K. AXL as immune regulator and therapeutic target in acute myeloid leukemia: From current progress to novel strategies. Exp. Hematol. Oncol. 2024, 13, 99. [Google Scholar] [CrossRef]
  173. Kubasch, A.S.; Peterlin, P.; Cluzeau, T.; Götze, K.S.; Sockel, K.; Teipel, R.; Jentzsch, M.; Attalah, H.; Sebert, M.; Chermat, F.; et al. Efficacy and safety of bemcentinib in patients with advanced myelodysplastic neoplasms or acute myeloid leukemia failing hypomethylating agents—The EMSCO phase II BERGAMO trial. Leukemia 2023, 37, 2309–2313. [Google Scholar] [CrossRef]
  174. Dave, F.; Herrera, K.; Lockley, A.; van de Weijer, L.L.; Henderson, S.; Sofela, A.A.; Hook, L.; Adams, C.L.; Ercolano, E.; Hilton, D.A.; et al. Targeting MERTK on Tumour Cells and Macrophages: A Potential Intervention for Sporadic and NF2-Related Meningioma and Schwannoma Tumours. Oncogene 2024, 43, 3049–3061. [Google Scholar] [CrossRef]
  175. Li, K.M.; Deng, L.G.; Xue, L.J.; Tan, C.; Yao, S.K. AXL Inhibition Prevents RPA2/CHK1-Mediated Homologous Recombination to Increase PARP Inhibitor Sensitivity in Hepatocellular Carcinoma. Heliyon 2024, 10, e36283. [Google Scholar] [CrossRef]
  176. Arechederra, M.; Bazai, S.K.; Abdouni, A.; Sequera, C.; Mead, T.J.; Richelme, S.; Daian, F.; Audebert, S.; Dono, R.; Lozano, A.; et al. ADAMTSL5 Is an Epigenetically Activated Gene Underlying Tumorigenesis and Drug Resistance in Hepatocellular Carcinoma. J. Hepatol. 2021, 74, 893–906. [Google Scholar] [CrossRef]
  177. Grøndal, S.M.; Tutusaus, A.; Boix, L.; Reig, M.; Blø, M.; Hodneland, L.; Gausdal, G.; Jackson, A.; Garcia de Frutos, P.; Lorens, J.B.; et al. Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH. Front. Immunol. 2024, 15, 1400553. [Google Scholar] [CrossRef] [PubMed]
  178. Danielli, S.G.; Wurth, J.; Morice, S.; Kisele, S.; Surdez, D.; Delattre, O.; Bode, P.K.; Wachtel, M.; Schäfer, B.W. Evaluation of the role of AXL in fusion-positive pediatric rhabdomyosarcoma identifies the small-molecule inhibitor bemcentinib (BGB324) as potent chemosensitizer. Mol. Cancer Ther. 2024, 23, 864–876. [Google Scholar] [CrossRef] [PubMed]
  179. Stewart, C.A.; Gay, C.M.; Ramkumar, K.; Cargill, K.R.; Cardnell, R.J.; Nilsson, M.B.; Heeke, S.; Park, E.M.; Kundu, S.T.; Diao, L.; et al. Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2-Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology. J. Thorac. Oncol. 2021, 16, 1821–1839. [Google Scholar] [CrossRef]
  180. Jordan, C.Z.; Tunbridge, M.; Husain, I.; Kitai, H.; Dilts, M.E.; Fay, O.K.; Abe, K.; Xiang, C.; Kwun, J.; Souma, T.; et al. AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival. JCI Insight 2024, 9, e178502. [Google Scholar] [CrossRef]
  181. Gelebart, P.; Eriksen Gjerstad, M.; Benjaminsen, S.; Han, J.; Karlsen, I.; Safont, M.M.; Leitch, C.; Fandalyuk, Z.; Popa, M.; Helgeland, L.; et al. Inhibition of a New AXL Isoform, AXL3, Induces Apoptosis of Mantle Cell Lymphoma Cells. Blood 2023, 142, 1478–1493. [Google Scholar] [CrossRef]
  182. Lv, H.; Sun, H.; Wang, L.; Yao, S.; Liu, D.; Zhang, X.; Pei, Z.; Zhou, J.; Wang, H.; Dai, J.; et al. Targeting CD301⁺ Macrophages Inhibits Endometrial Fibrosis and Improves Pregnancy Outcome. EMBO Mol. Med. 2023, 15, e17601. [Google Scholar] [CrossRef] [PubMed]
  183. Batur, T.; Argundogan, A.; Keles, U.; Mutlu, Z.; Alotaibi, H.; Senturk, S.; Ozturk, M. AXL Knock-Out in SNU475 Hepatocellular Carcinoma Cells Provides Evidence for Lethal Effect Associated with G2 Arrest and Polyploidization. Int. J. Mol. Sci. 2021, 22, 13247. [Google Scholar] [CrossRef]
  184. Bian, Q.; Anderson, J.C.; Zhang, X.W.; Huang, Z.Q.; Ebefors, K.; Nyström, J.; Hall, S.; Novak, L.; Julian, B.A.; Willey, C.D.; et al. Mesangioproliferative Kidney Diseases and Platelet-Derived Growth Factor-Mediated AXL Phosphorylation. Kidney Med. 2021, 3, 1003–1013.e1. [Google Scholar] [CrossRef]
  185. Beitzen-Heineke, A.; Berenbrok, N.; Waizenegger, J.; Paesler, S.; Gensch, V.; Udonta, F.; Vargas Delgado, M.E.; Engelmann, J.; Hoffmann, F.; Schafhausen, P.; et al. AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms. Hemasphere 2021, 5, e630. [Google Scholar] [CrossRef] [PubMed]
  186. Hoel, A.; Osman, T.; Hoel, F.; Elsaid, H.; Chen, T.; Landolt, L.; Babickova, J.; Tronstad, K.J.; Lorens, J.B.; Gausdal, G.; et al. Axl-Inhibitor Bemcentinib Alleviates Mitochondrial Dysfunction in the Unilateral Ureter Obstruction Murine Model. J. Cell. Mol. Med. 2021, 25, 7407–7417. [Google Scholar] [CrossRef] [PubMed]
  187. Steiner, C.A.; Rodansky, E.S.; Johnson, L.A.; Berinstein, J.A.; Cushing, K.C.; Huang, S.; Spence, J.R.; Higgins, P.D.R. AXL Is a Potential Target for the Treatment of Intestinal Fibrosis. Inflamm. Bowel Dis. 2021, 27, 303–316. [Google Scholar] [CrossRef] [PubMed]
  188. Bae, C.A.; Ham, I.H.; Oh, H.J.; Lee, D.; Woo, J.; Son, S.Y.; Yoon, J.H.; Lorens, J.B.; Brekken, R.A.; Kim, T.M.; et al. Inhibiting the GAS6/AXL Axis Suppresses Tumor Progression by Blocking the Interaction between Cancer-Associated Fibroblasts and Cancer Cells in Gastric Carcinoma. Gastric Cancer 2020, 23, 824–836. [Google Scholar] [CrossRef]
  189. Flem-Karlsen, K.; Nyakas, M.; Farstad, I.N.; McFadden, E.; Wernhoff, P.; Jacobsen, K.D.; Flørenes, V.A.; Mælandsmo, G.M. Soluble AXL as a Marker of Disease Progression and Survival in Melanoma. PLoS ONE 2020, 15, e0227187. [Google Scholar] [CrossRef]
  190. Tutusaus, A.; de Gregorio, E.; Cucarull, B.; Cristóbal, H.; Aresté, C.; Graupera, I.; Coll, M.; Colell, A.; Gausdal, G.; Lorens, J.B.; et al. A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target. Cell. Mol. Gastroenterol. Hepatol. 2020, 9, 349–368. [Google Scholar] [CrossRef]
  191. Malvankar, C.; Kumar, D. AXL kinase inhibitors—A prospective model for medicinal chemistry strategies in anticancer drug discovery. Biochim. Biophys. Acta Rev. Cancer 2022, 1877, 188786. [Google Scholar] [CrossRef]
  192. Loges, S.; Heuser, M.; Chromik, J.; Vigil, C.E.; Paschka, P.; Ben-Batalla, I.; Akyüz, N.; Micklem, D.; Holt, R.; Brown, A.; et al. Final analysis of the dose escalation, expansion and biomarker correlations in the Ph I/II trial BGBC003 with the selective oral AXL inhibitor bemcentinib (BGB324) in relapsed/refractory AML and MDS. Blood 2018, 132 (Suppl. S1), 2672. [Google Scholar] [CrossRef]
  193. Budha, N.R.; Ji, T.; Musib, L.; Eppler, S.; Dresser, M.; Chen, Y.; Jin, J.Y. Evaluation of cytochrome P450 3A4-mediated drug-drug interaction potential for cobimetinib using physiologically based pharmacokinetic modeling and simulation. Clin. Pharmacokinet. 2016, 55, 1435–1445. [Google Scholar] [CrossRef]
  194. Guengerich, F.P. Inhibition of cytochrome P450 enzymes by drugs—Molecular basis and practical applications. Biomol. Ther. 2022, 30, 1–18. [Google Scholar] [CrossRef]
  195. Chen, Y.; Dong, X.; Wang, Q.; Liu, Z.; Dong, X.; Shi, S.; Xiao, H. Factors influencing the steady-state plasma concentration of imatinib mesylate in patients with gastrointestinal stromal tumors and chronic myeloid leukemia. Front. Pharmacol. 2020, 11, 569843. [Google Scholar] [CrossRef]
  196. Bemcentinib: A Promising New Cancer Treatment. Available online: https://clinicaltrials.eu/inn/bemcentinib/ (accessed on 9 June 2025).
  197. Wium, M.; Ajayi-Smith, A.F.; Paccez, J.D.; Zerbini, L.F. The role of the receptor tyrosine kinase Axl in carcinogenesis and development of therapeutic resistance: An overview of molecular mechanisms and future applications. Cancers 2021, 13, 1521. [Google Scholar] [CrossRef] [PubMed]
  198. Identification of Predictive and Pharmacodynamic Biomarkers Associated with the First-in-Class Selective AXL Inhibitor Bemcentinib Across Multiple Phase II Clinical Trials. Available online: https://www.asco.org/abstracts-presentations/ABSTRACT228259 (accessed on 9 June 2025).
  199. Bemcentinib (BGB324) in Combination with Pembrolizumab in Patients with Advanced NSCLC. Available online: https://clinicaltrials.gov/study/NCT03184571 (accessed on 9 June 2025).
  200. Spicer, J.; Helland, Å.; Carcereny, E.; Arriola, E.; Dómine Gomez, M.; Trigo Perez, J.M.; Thompson, J.; Strauss, J.; Ortega Granados, A.L.; Felip, E.; et al. A PhII study of bemcentinib, a first-in-class selective AXL kinase inhibitor, in combination with pembrolizumab in pts with previously-treated advanced NSCLC: Updated clinical & translational analysis. J. Immunother. Cancer 2020, 8 (Suppl. S2), A362. [Google Scholar] [CrossRef]
  201. Axl Inhibitors for Aggressive Disease. Available online: https://bgbwebpagefiles.fra1.cdn.digitaloceanspaces.com/wp-content/uploads/2020/01/BerGenBio-corp-Jan-2020.pdf (accessed on 9 June 2025).
  202. Phase 1b/2a Trial of Bemcentinib and SOC Doses First Patient with STK11m NSCLC. Available online: https://www.targetedonc.com/view/phase-1b-2a-trial-of-bemcentinib-and-soc-doses-first-patient-with-stk11m-nsclc (accessed on 9 June 2025).
  203. Malekinejad, Z.; Baghbanzadeh, A.; Nakhlband, A.; Baradaran, B.; Jafari, S.; Bagheri, Y.; Raei, F.; Montazersaheb, S.; Farahzadi, R. Recent clinical findings on the role of kinase inhibitors in COVID-19 management. Life Sci. 2022, 306, 120809. [Google Scholar] [CrossRef]
  204. Davis, F.M.; Stewart, T.A.; Thompson, E.W.; Monteith, G.R. Targeting EMT in cancer: Opportunities for pharmacological intervention. Trends Pharmacol. Sci. 2014, 35, 479–488. [Google Scholar] [CrossRef]
  205. Zhan, M.; Liu, D.; Yao, L.; Wang, W.; Zhang, R.; Xu, Y.; Wang, Z.; Yan, Q.; Fang, Q.; Du, J.; et al. Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway. Transplantation 2024, 108, e357–e369. [Google Scholar] [CrossRef]
  206. Zuo, R.C.; Apolo, A.B.; DiGiovanna, J.J.; Parnes, H.L.; Keen, C.M.; Nanda, S.; Dahut, W.L.; Cowen, E.W. Cutaneous Adverse Effects Associated with the Tyrosine-Kinase Inhibitor Cabozantinib. JAMA Dermatol. 2015, 151, 170–177. [Google Scholar] [CrossRef] [PubMed]
  207. Loges, S.; Heuser, M.; Chromik, J.; Sutamtewagul, G.; Kapp-Schwoerer, S.; Crugnola, M.; Di Renzo, N.; Lemoli, R.; Mattei, D.; Fiedler, W.; et al. Bemcentinib as Monotherapy and in Combination with Low-Dose Cytarabine in Acute Myeloid Leukemia Patients Unfit for Intensive Chemotherapy: A Phase 1b/2a Trial. Nat. Commun. 2025, 16, 2846. [Google Scholar] [CrossRef] [PubMed]
  208. Ito, Y.; Shibata, S.; Koyama, A.; Li, L.; Sugimoto, E.; Taira, H.; Mizuno, Y.; Awaji, K.; Sato, S. Decreased Epidermal AXL Expression and Increased Infiltration of AXL-Expressing Dendritic Cells in Psoriasis. J. Cutan. Immunol. Allergy 2023, 6, 208–218. [Google Scholar] [CrossRef]
  209. Bumm, C.V.; Folwaczny, M.; Wölfle, U.C. Necrotizing Periodontitis or Medication-Related Osteonecrosis of the Jaw (MRONJ) in a Patient Receiving Bemcentinib—A Case Report. Oral Maxillofac. Surg. 2020, 24, 353–358. [Google Scholar] [CrossRef]
  210. Zhang, B.; Wu, Q.; Zhou, Y.L.; Guo, X.; Ge, J.; Fu, J. Immune-Related Adverse Events from Combination Immunotherapy in Cancer Patients: A Comprehensive Meta-Analysis of Randomized Controlled Trials. Int. Immunopharmacol. 2018, 63, 292–298. [Google Scholar] [CrossRef]
  211. Xie, Y.; Wu, H.; He, Y.; Liu, L.; Huang, I.B.; Zhou, L.; Lin, C.Y.; Leung, R.W.; Loh, J.J.; Lee, T.K.; et al. Targeting AXL Induces Tumor-Intrinsic Immunogenic Response in Tyrosine Kinase Inhibitor-Resistant Liver Cancer. Cell Death Dis. 2024, 15, 110. [Google Scholar] [CrossRef] [PubMed]
  212. Liu, Z.; Chen, L.; Zhang, J.; Yang, J.; Xiao, X.; Shan, L.; Mao, W. Recent Discovery and Development of AXL Inhibitors as Antitumor Agents. Eur. J. Med. Chem. 2024, 272, 116475. [Google Scholar] [CrossRef] [PubMed]
  213. Tomuleasa, C.; Tigu, A.B.; Munteanu, R.; Moldovan, C.S.; Kegyes, D.; Onaciu, A.; Gulei, D.; Ghiaur, G.; Einsele, H.; Croce, C.M. Therapeutic Advances of Targeting Receptor Tyrosine Kinases in Cancer. Signal Transduct. Target Ther. 2024, 9, 201. [Google Scholar] [CrossRef]
  214. Shah, K.; Gopal, K.; Kumar, S.; Saha, S. Emerging AXL Inhibitors in Oncology: Chemical and Biological Advances in Targeted Cancer Therapy. Anticancer Agents Med. Chem. 2025, 25, 460–467. [Google Scholar] [CrossRef]
  215. Zhao, H.; Sun, Y.; Feng, H.; Cai, J.; Liu, Y.; Li, Y.; Chen, S.; Zhou, Z.; Du, Y.; Zeng, X.; et al. PFKP Silencing Suppresses Tumor Growth via the AXL-MET Axis. Int. J. Biol. Sci. 2024, 20, 6056–6072. [Google Scholar] [CrossRef]
  216. Li, H.; Liu, Z.; Liu, L.; Zhang, H.; Han, C.; Girard, L.; Park, H.; Zhang, A.; Dong, C.; Ye, J.; et al. AXL Targeting Restores PD-1 Blockade Sensitivity of STK11/LKB1 Mutant NSCLC through Expansion of TCF1⁺ CD8 T Cells. Cell Rep. Med. 2022, 3, 100554. [Google Scholar] [CrossRef]
  217. Zhou, X.; Zeng, L.; Huang, Z.; Ruan, Z.; Yan, H.; Zou, C.; Xu, S.; Zhang, Y. Strategies Beyond 3rd EGFR-TKI Acquired Resistance: Opportunities and Challenges. Cancer Med. 2025, 14, e70921. [Google Scholar] [CrossRef] [PubMed]
  218. Wu, X.; Liu, X.; Koul, S.; Lee, C.Y.; Zhang, Z.; Halmos, B. AXL kinase as a novel target for cancer therapy. Oncotarget 2014, 5, 9546–9563. [Google Scholar] [CrossRef]
  219. Elkabets, M.; Vora, S.; Juric, D.; Morse, N.; Mino-Kenudson, M.; Muranen, T.; Tao, J.; Campos, A.B.; Rodon, J.; Ibrahim, Y.H.; et al. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci. Transl. Med. 2013, 5, 196ra99. [Google Scholar] [CrossRef]
  220. Zabludoff, S.D.; Deng, C.; Grondine, M.R.; Sheehy, A.M.; Ashwell, S.; Caleb, B.L.; Green, S.; Haye, H.R.; Horn, C.L.; Janetka, J.W.; et al. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol. Cancer Ther. 2008, 7, 2955–2966. [Google Scholar] [CrossRef]
  221. BerGenBio to Present Interim Clinical and Biomarker Data with Selective AXL Inhibitor Bemcentinib in AML and MDS at EHA. Available online: https://www.prnewswire.com/news-releases/bergenbio-to-present-interim-clinical-and-biomarker-data-with-selective-axl-inhibitor-bemcentinib-in-aml-and-mds-at-eha-300650898.html (accessed on 9 June 2025).
  222. Annexes to the Annual Report of the European Medicines Agency 2024. Available online: https://www.ema.europa.eu/en/documents/annual-report/annexes-2024-annual-report-european-medicines-agency_en.pdf (accessed on 9 June 2025).
  223. Yang, Y.; Li, S.; Wang, Y.; Zhao, Y.; Li, Q. Protein tyrosine kinase inhibitor resistance in malignant tumors: Molecular mechanisms and future perspective. Signal Transduct Target Ther. 2022, 7, 329. [Google Scholar] [CrossRef]
  224. Myers, S.H.; Brunton, V.G.; Unciti-Broceta, A. AXL Inhibitors in Cancer: A Medicinal Chemistry Perspective. J. Med. Chem. 2016, 59, 3593–3608. [Google Scholar] [CrossRef]
  225. Foley, C.N.; Qu, S.; Paladugu, S.R.; Lamani, M.; Grange, R.; Sharif, E.U.; Thomas, J.; Nareddy, P.; Zhao, G.; Chen, Y.; et al. Discovery and Characterization of Potent, Selective, and Orally Bioavailable 7-Azaindazole AXL Receptor Tyrosine Kinase Inhibitors. J. Med. Chem. 2025, 68, 10677–10703. [Google Scholar] [CrossRef] [PubMed]
  226. Study of Bemcentinib with Pembrolizumab, Carboplatin, and Pemetrexed for Patients with Advanced or Metastatic Non-Small Cell Lung Cancer with STK11 Mutation. Available online: https://clinicaltrials.eu/trial/study-of-bemcentinib-with-pembrolizumab-carboplatin-and-pemetrexed-for-patients-with-advanced-or-metastatic-non-small-cell-lung-cancer-with-stk11-mutation/ (accessed on 5 June 2025).
  227. Tang, Y.; Zang, H.; Wen, Q.; Fan, S. AXL in cancer: A modulator of drug resistance and therapeutic target. J. Exp. Clin. Cancer Res. 2023, 42, 148. [Google Scholar] [CrossRef] [PubMed]
  228. Lheureux, S.; Denoyelle, C.; Ohashi, P.S.; De Bono, J.S.; Mottaghy, F.M. Molecularly targeted therapies in cancer: A guide for the nuclear medicine physician. Eur. J. Nucl. Med. Mol. Imaging 2017, 44 (Suppl. S1), 41–54. [Google Scholar] [CrossRef]
  229. Pfohl, U.; Pflaume, A.; Regenbrecht, M.; Finkler, S.; Graf Adelmann, Q.; Reinhard, C.; Regenbrecht, C.R.A.; Wedeken, L. Precision Oncology Beyond Genomics: The Future Is Here—It Is Just Not Evenly Distributed. Cells 2021, 10, 928. [Google Scholar] [CrossRef]
  230. AXL Inhibition Improves BRAF-Targeted Treatment in Melanoma. Cutaneous Metastatic Melanoma Searching for Biomarkers and New Treatment. Nyakas, M.S. Available online: https://www.duo.uio.no/bitstream/handle/10852/117853/PhD-Nyakas-2025.pdf%3Fsequence%3D1%26isAllowed%3Dy&ved=2ahUKEwjH3Nzs1IGOAxUdSvEDHYKrOL8QFnoECB4QAQ&usg=AOvVaw0as92GmBq8gp0KVvZzw7aW (accessed on 9 June 2025).
  231. Riillo, C.; Polerà, N.; Di Martino, M.T.; Juli, G.; Hokanson, C.A.; Odineca, T.; Signorelli, S.; Grillone, K.; Ascrizzi, S.; Mancuso, A.; et al. A Pronectin™ AXL-Targeted First-in-Class Bispecific T Cell Engager (pAXLxCD3ε) for Ovarian Cancer. J. Transl. Med. 2023, 21, 301. [Google Scholar] [CrossRef] [PubMed]
  232. Ricketts, T.D.; Prieto-Dominguez, N.; Gowda, P.S.; Ubil, E. Mechanisms of Macrophage Plasticity in the Tumor Environment: Manipulating Activation State to Improve Outcomes. Front. Immunol. 2021, 12, 642285. [Google Scholar] [CrossRef]
  233. Onken, J.; Torka, R.; Korsing, S.; Radke, J.; Krementeskaia, I.; Nieminen, M.; Bai, X.; Ullrich, A.; Heppner, F.; Vajkoczy, P. Inhibiting Receptor Tyrosine Kinase AXL with Small Molecule Inhibitor BMS-777607 Reduces Glioblastoma Growth, Migration, and Invasion In Vitro and In Vivo. Oncotarget 2016, 7, 9876–9889. [Google Scholar] [CrossRef]
  234. Li, M.C.; Lai, Y.L.; Kuo, P.H.; Reddy, J.S.; Chen, C.M.; Manimala, J.; Wang, P.C.; Wu, M.S.; Chang, C.Y.; Yang, C.M.; et al. Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment. J. Med. Chem. 2024, 67, 10906–10927. [Google Scholar] [CrossRef]
  235. Sakemura, R.L.; Hefazi, M.; Cox, M.J.; Siegler, E.L.; Sinha, S.; Hansen, M.J.; Stewart, C.M.; Feigin, J.M.; Manriquez Roman, C.; Schick, K.J.; et al. AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells. Cancer Immunol. Res. 2023, 11, 1222–1236. [Google Scholar] [CrossRef]
  236. Datta, A.; Bahlmann, L.C.; Gong, D.N.; Tevonian, E.N.; Lorens, J.B.; Lauffenburger, D.A. Axl Inhibitor-Mediated Reprogramming of the Myeloid Compartment of the In Vitro Tumor Microenvironment Is Influenced by Prior Targeted Therapy Treatment. Front. Immunol. 2025, 16, 1601420. [Google Scholar] [CrossRef]
  237. Rayford, A.; Gärtner, F.; Ramnefjell, M.P.; Lorens, J.B.; Micklem, D.R.; Aanerud, M.; Engelsen, A.S.T. AXL Expression Reflects Tumor-Immune Cell Dynamics Impacting Outcome in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitor Monotherapy. Front. Immunol. 2024, 15, 1444007. [Google Scholar] [CrossRef] [PubMed]
  238. Patel, H.; Yacoub, N.; Mishra, R.; White, A.; Long, Y.; Alanazi, S.; Garrett, J.T. Current Advances in the Treatment of BRAF-Mutant Melanoma. Cancers 2020, 12, 482. [Google Scholar] [CrossRef]
  239. Ding, S.-Y.; Yang, Y.-X.; Liu, C.; Quan, X.-Y.; Zhao, Z.-H.; Jin, C.-H. Synthesis and Biological Evaluation of Sulfonamide Derivatives Containing Imidazole Moiety as ALK5 Inhibitors. Mol. Divers. 2025, 29, 2143–2156. [Google Scholar] [CrossRef]
  240. Massagué, J. TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 2012, 13, 616–630. [Google Scholar] [CrossRef]
  241. Derynck, R.; Zhang, Y.E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 2003, 425, 577–584. [Google Scholar] [CrossRef] [PubMed]
  242. Yingling, J.M.; McMillen, W.T.; Yan, L.; Huang, H.; Sawyer, J.S.; Graff, J.; Clawson, D.K.; Britt, K.S.; Anderson, B.D.; Beight, D.W.; et al. Preclinical Assessment of Galunisertib (LY2157299 Monohydrate), a First-in-Class Transforming Growth Factor-β Receptor Type I Inhibitor. Oncotarget 2017, 9, 6659–6677. [Google Scholar] [CrossRef]
  243. Yen, Y.T.; Zhang, Z.; Chen, A.; Qiu, Y.; Liu, Q.; Wang, Q.; Li, C.; Wang, C.; Qian, X.; Shao, J.; et al. Enzymatically Responsive Nanocarriers Targeting PD-1 and TGF-β Pathways Reverse Immunotherapeutic Resistance and Elicit Robust Therapeutic Efficacy. J. Nanobiotechnol. 2025, 23, 124. [Google Scholar] [CrossRef] [PubMed]
  244. Yu, E.J.; Bell, D.W. The Endometrial Cancer A230V-ALK5 (TGFBR1) Mutant Attenuates TGF-β Signaling and Exhibits Reduced In Vitro Sensitivity to ALK5 Inhibitors. PLoS ONE 2024, 19, e0312806. [Google Scholar] [CrossRef]
  245. Ikushima, H.; Miyazono, K. TGFβ signalling: A complex web in cancer progression. Nat. Rev. Cancer 2010, 10, 415–424. [Google Scholar] [CrossRef]
  246. David, C.J.; Massagué, J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat. Rev. Mol. Cell Biol. 2018, 19, 419–435. [Google Scholar] [CrossRef]
  247. Bataller, A.; Montalban-Bravo, G.; Soltysiak, K.A.; Garcia-Manero, G. The role of TGFβ in hematopoiesis and myeloid disorders. Leukemia 2019, 33, 1076–1089. [Google Scholar] [CrossRef] [PubMed]
  248. Levy, L.; Hill, C.S. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol. Cell. Biol. 2005, 25, 8108–8125. [Google Scholar] [CrossRef] [PubMed]
  249. Ihn, H. Autocrine TGF-β Signaling in the Pathogenesis of Systemic Sclerosis. J. Dermatol. Sci. 2008, 49, 103–113. [Google Scholar] [CrossRef] [PubMed]
  250. Giampieri, S.; Manning, C.; Hooper, S.; Jones, L.; Hill, C.S.; Sahai, E. Localized and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nat. Cell Biol. 2009, 11, 1287–1296. [Google Scholar] [CrossRef]
  251. Delle Cave, D.; Mangini, M.; Tramontano, C.; De Stefano, L.; Corona, M.; Rea, I.; De Luca, A.C.; Lonardo, E. Hybrid Biosilica Nanoparticles for In Vivo Targeted Inhibition of Colorectal Cancer Growth and Label-Free Imaging. Int. J. Nanomed. 2024, 19, 12079–12098. [Google Scholar] [CrossRef]
  252. Derynck, R.; Akhurst, R.J.; Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nat. Genet. 2001, 29, 117–129. [Google Scholar] [CrossRef]
  253. Giannelli, G.; Villa, E.; Lahn, M. Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma. Cancer Res. 2014, 74, 1890–1894. [Google Scholar] [CrossRef]
  254. Bloom, M.; Podder, S.; Dang, H.; Lin, D. Advances in Immunotherapy in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2025, 26, 1936. [Google Scholar] [CrossRef]
  255. Scialpi, R.; Espinosa-Sotelo, R.; Bertran, E.; Dituri, F.; Giannelli, G.; Fabregat, I. New Hepatocellular Carcinoma (HCC) Primary Cell Cultures as Models for Exploring Personalized Anti-TGF-β Therapies Based on Tumor Characteristics. Int. J. Mol. Sci. 2025, 26, 2430. [Google Scholar] [CrossRef] [PubMed]
  256. Panzarini, E.; Leporatti, S.; Tenuzzo, B.A.; Quarta, A.; Hanafy, N.A.N.; Giannelli, G.; Moliterni, C.; Vardanyan, D.; Sbarigia, C.; Fidaleo, M.; et al. Therapeutic Effect of Polymeric Nanomicelles Formulation of LY2157299-Galunisertib on CCl4-Induced Liver Fibrosis in Rats. J. Pers. Med. 2022, 12, 1812. [Google Scholar] [CrossRef] [PubMed]
  257. Maas, R.J.A.; Hoogstad-van Evert, J.S.; Hagemans, I.M.; Brummelman, J.; van Ens, D.; de Jonge, P.K.J.D.; Hooijmaijers, L.; Mahajan, S.; van der Waart, A.B.; Hermans, C.K.J.C.; et al. Increased Peritoneal TGF-β1 Is Associated with Ascites-Induced NK-Cell Dysfunction and Reduced Survival in High-Grade Epithelial Ovarian Cancer. Front. Immunol. 2024, 15, 1448041. [Google Scholar] [CrossRef] [PubMed]
  258. Hou, C.; Yang, Y.; Wang, P.; Xie, H.; Jin, S.; Zhao, L.; Wu, G.; Xing, H.; Chen, H.; Liu, B.; et al. CCDC113 Promotes Colorectal Cancer Tumorigenesis and Metastasis via TGF-β Signaling Pathway. Cell Death Dis. 2024, 15, 666. [Google Scholar] [CrossRef]
  259. Infante, A.; Alcorta-Sevillano, N.; Macías, I.; Cabodevilla, L.; Medhat, D.; Lafaver, B.; Crawford, T.K.; Phillips, C.L.; Bueno, A.M.; Sagastizabal, B.; et al. Galunisertib Downregulates Mutant Type I Collagen Expression and Promotes MSCs Osteogenesis in Pediatric Osteogenesis Imperfecta. Biomed. Pharmacother. 2024, 175, 116725. [Google Scholar] [CrossRef]
  260. Jank, B.J.; Lenz, T.; Haas, M.; Kadletz-Wanke, L.; Campion, N.J.; Schnoell, J.; Heiduschka, G.; Macfelda, K. Radiosensitizing Effect of Galunisertib, a TGF-β Receptor I Inhibitor, on Head and Neck Squamous Cell Carcinoma In Vitro. Investig. New Drugs 2022, 40, 478–486. [Google Scholar] [CrossRef]
  261. Gu, S.; Feng, X.H. TGF-β Signaling in Cancer. Acta Biochim. Biophys. Sin. 2018, 50, 941–949. [Google Scholar] [CrossRef]
  262. Fujiwara, Y.; Nokihara, H.; Yamada, Y.; Yamamoto, N.; Sunami, K.; Utsumi, H.; Asou, H.; Takahashi, O.; Ogasawara, K.; Gueorguieva, I.; et al. Phase 1 Study of Galunisertib, a TGF-beta Receptor I Kinase Inhibitor, in Japanese Patients with Advanced Solid Tumors. Cancer Chemother. Pharmacol. 2015, 76, 1143–1152. [Google Scholar] [CrossRef]
  263. Faivre, S.; Santoro, A.; Kelley, R.K.; Gane, E.; Costentin, C.E.; Gueorguieva, I.; Smith, C.; Cleverly, A.; Lahn, M.M.; Raymond, E.; et al. Novel Transforming Growth Factor Beta Receptor I Kinase Inhibitor Galunisertib (LY2157299) in Advanced Hepatocellular Carcinoma. Liver Int. 2019, 39, 1468–1477. [Google Scholar] [CrossRef]
  264. Feng, X.H.; Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 2005, 21, 659–693. [Google Scholar] [CrossRef]
  265. Heldin, C.H.; Moustakas, A. Signaling receptors for TGF-β family members. Cold Spring Harb. Perspect. Biol. 2016, 8, a022053. [Google Scholar] [CrossRef] [PubMed]
  266. Zhang, Q.; Hou, X.; Evans, B.J.; VanBlaricom, J.L.; Weroha, S.J.; Cliby, W.A. LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer. Cancers 2018, 10, 260. [Google Scholar] [CrossRef] [PubMed]
  267. Zhang, J.; Deng, Y.T.; Liu, J.; Gan, L.; Jiang, Y. Role of Transforming Growth Factor-β1 Pathway in Angiogenesis Induced by Chronic Stress in Colorectal Cancer. Cancer Biol. Ther. 2024, 25, 2366451. [Google Scholar] [CrossRef]
  268. Yin, L. Combination Therapy of Bevacizumab and Galunisertib Extends TVN Time Window. Mol. Ther. Oncol. 2024, 32, 200888. [Google Scholar] [CrossRef]
  269. Kuburich, N.A.; Sabapathy, T.; Demestichas, B.R.; Maddela, J.J.; den Hollander, P.; Mani, S.A. Proactive and reactive roles of TGF-β in cancer. Semin. Cancer Biol. 2023, 95, 120–139. [Google Scholar] [CrossRef]
  270. Yang, L.L.; Chen, X.; Huang, K.T.; Wang, J.L. Global Trends in Hepatocellular Carcinoma and TGF-β Research: A Bibliometric and Visualization Analysis from 2000 to 2024. Curr. Protein Pept. Sci. 2025, (Online ahead of print). 1–19. [Google Scholar] [CrossRef]
  271. Giannelli, G.; Santoro, A.; Kelley, R.K.; Gane, E.; Paradis, V.; Cleverly, A.; Smith, C.; Estrem, S.T.; Man, M.; Wang, S.; et al. Biomarkers and Overall Survival in Patients with Advanced Hepatocellular Carcinoma Treated with TGF-βRI Inhibitor Galunisertib. PLoS ONE 2020, 15, e0222259. [Google Scholar] [CrossRef]
  272. Gungor, M.Z.; Uysal, M.; Senturk, S. The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications. Cancers 2022, 14, 940. [Google Scholar] [CrossRef]
  273. Brandes, A.A.; Carpentier, A.F.; Kesari, S.; Sepulveda-Sanchez, J.M.; Wheeler, H.R.; Chinot, O.; Cher, L.; Steinbach, J.P.; Capper, D.; Specenier, P.; et al. A Phase II Randomized Study of Galunisertib Monotherapy or Galunisertib Plus Lomustine Compared with Lomustine Monotherapy in Patients with Recurrent Glioblastoma. Neuro Oncol. 2016, 18, 1146–1156. [Google Scholar] [CrossRef] [PubMed]
  274. Hadizadeh, M.; AminJafari, A.; Parvizpour, S.; Ghasemi, S. Novel Targets to Overcome Antiangiogenesis Therapy Resistance in Glioblastoma Multiforme: Systems Biology Approach and Suggestion of Therapy by Galunisertib. Cell Biol. Int. 2022, 46, 1649–1660. [Google Scholar] [CrossRef] [PubMed]
  275. Tauriello, D.V.F.; Palomo-Ponce, S.; Stork, D.; Berenguer-Llergo, A.; Badia-Ramentol, J.; Iglesias, M.; Sevillano, M.; Ibiza, S.; Cañellas, A.; Hernando-Momblona, X.; et al. TGFβ Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis. Nature 2018, 554, 538–543. [Google Scholar] [CrossRef]
  276. Yang, H.H.; Liu, J.W.; Lee, J.H.; Harn, H.J.; Chiou, T.W. Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor. Int. J. Mol. Sci. 2021, 22, 8125. [Google Scholar] [CrossRef] [PubMed]
  277. Pietrobono, S.; Bertolini, M.; De Vita, V.; Sabbadini, F.; Fazzini, F.; Frusteri, C.; Scarlato, E.; Mangiameli, D.; Quinzii, A.; Casalino, S.; et al. CCL3 Predicts Exceptional Response to TGFβ Inhibition in Basal-Like Pancreatic Cancer Enriched in LIF-Producing Macrophages. NPJ Precis. Oncol. 2024, 8, 246. [Google Scholar] [CrossRef]
  278. Neuzillet, C.; Tijeras-Raballand, A.; Cohen, R.; Cros, J.; Faivre, S.; Raymond, E.; de Gramont, A. Targeting the TGFβ Pathway for Cancer Therapy. Pharmacol. Ther. 2015, 147, 22–31. [Google Scholar] [CrossRef] [PubMed]
  279. Ganesh, K.; Massagué, J. TGF-β Inhibition and Immunotherapy: Checkmate. Immunity 2018, 48, 626–628. [Google Scholar] [CrossRef]
  280. Shi, L.; Sheng, J.; Wang, M.; Luo, H.; Zhu, J.; Zhang, B.; Liu, Z.; Yang, X. Combination Therapy of TGF-β Blockade and Commensal-Derived Probiotics Provides Enhanced Antitumor Immune Response and Tumor Suppression. Theranostics 2019, 9, 4115–4129. [Google Scholar] [CrossRef]
  281. Study of Galunisertib and Capecitabine for Patients with Advanced Chemotherapy-Resistant Colorectal Cancer with Peritoneal Metastases. Available online: https://clinicaltrials.eu/trial/study-of-galunisertib-and-capecitabine-for-patients-with-advanced-chemotherapy-resistant-colorectal-cancer-with-peritoneal-metastases/ (accessed on 9 June 2025).
  282. Tschernia, N.P.; Gulley, J.L. Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy. BioDrugs 2022, 36, 153–180. [Google Scholar] [CrossRef]
  283. Chiechi, A.; Waning, D.L.; Stayrook, K.R.; Buijs, J.T.; Guise, T.A.; Mohammad, K.S. Role of TGF-β in Breast Cancer Bone Metastases. Adv. Biosci. Biotechnol. 2013, 4, 15–30. [Google Scholar] [CrossRef]
  284. Peterson, J.M.; Jay, J.W.; Wang, Y.; Joglar, A.A.; Prasai, A.; Palackic, A.; Wolf, S.E.; El Ayadi, A. Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts. Int. J. Mol. Sci. 2022, 23, 6689. [Google Scholar] [CrossRef]
  285. Zhang, Y.E. Non-Smad pathways in TGF-β signaling. Cell Res. 2009, 19, 128–139. [Google Scholar] [CrossRef]
  286. Jiang, J.-H.; Deng, P. Discovery of New Inhibitors of Transforming Growth Factor-Beta Type 1 Receptor by Utilizing Docking and Structure-Activity Relationship Analysis. Int. J. Mol. Sci. 2019, 20, 4090. [Google Scholar] [CrossRef]
  287. Fang, Z.; Zhang, W.; Wang, H.; Zhang, C.; Li, J.; Chen, W.; Xu, X.; Wang, L.; Ma, M.; Zhang, S.; et al. Helicobacter pylori Promotes Gastric Cancer Progression by Activating the TGF-β/Smad2/EMT Pathway through HKDC1. Cell. Mol. Life Sci. 2024, 81, 453. [Google Scholar] [CrossRef]
  288. Mao, Y.; Xu, W.; Chen, L.; Liao, H. Computational Drug Repurposing Screening Targeting Profibrotic Cytokine in Acute Respiratory Distress Syndrome. Cell Biochem. Biophys. 2025, 83, 3877–3888. [Google Scholar] [CrossRef]
  289. de Vasconcellos, J.F.; Westbrook, P.; Dingle, M.; Dimtchev, A.; Raiciulescu, S.; Schellhase, C.W.; Piscoya, A.; Putko, R.; Bedrin, M.; Cole, H.; et al. Preclinical validation of TGFβ inhibitors as a novel therapeutic strategy for post-traumatic heterotopic ossification. Sci. Rep. 2025, 15, 14277. [Google Scholar] [CrossRef]
  290. Heldin, C.H.; Vanlandewijck, M.; Moustakas, A. Regulation of EMT by TGFβ in Cancer. FEBS Lett. 2012, 586, 1959–1970. [Google Scholar] [CrossRef]
  291. Principe, D.R.; DeCant, B.; Mascariñas, E.; Wayne, E.A.; Diaz, A.M.; Akagi, N.; Hwang, R.; Pasche, B.; Dawson, D.W.; Fang, D.; et al. TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res. 2016, 76, 2525–2539. [Google Scholar] [CrossRef] [PubMed]
  292. Imtiaz, S.; Ferdous, U.T.; Nizela, A.; Hasan, A.; Shakoor, A.; Zia, A.W.; Uddin, S. Mechanistic Study of Cancer Drug Delivery: Current Techniques, Limitations, and Future Prospects. Eur. J. Med. Chem. 2025, 290, 117535. [Google Scholar] [CrossRef] [PubMed]
  293. Gulley, J.L.; Schlom, J.; Barcellos-Hoff, M.H.; Wang, X.J.; Seoane, J.; Audhuy, F.; Lan, Y.; Dussault, I.; Moustakas, A. Dual Inhibition of TGF-β and PD-L1: A Novel Approach to Cancer Treatment. Mol. Oncol. 2022, 16, 2117–2134. [Google Scholar] [CrossRef] [PubMed]
  294. Castiglioni, A.; Yang, Y.; Williams, K.; Gogineni, A.; Lane, R.S.; Wang, A.W.; Shyer, J.A.; Zhang, Z.; Mittman, S.; Gutierrez, A.; et al. Combined PD-L1/TGFβ Blockade Allows Expansion and Differentiation of Stem Cell-Like CD8 T Cells in Immune Excluded Tumors. Nat. Commun. 2023, 14, 4703. [Google Scholar] [CrossRef]
  295. Seoane, J.; Gomis, R.R. TGF-β Family Signaling in Tumor Suppression and Cancer Progression. Cold Spring Harb. Perspect. Biol. 2017, 9, a022277. [Google Scholar] [CrossRef]
  296. Alsaffar, R.M.; Ali, S.; Rashid, S.; Rashid, S.M.; Majid, S.; Rehman, M.U. Immunomodulation: An Immune Regulatory Mechanism in Carcinoma Therapeutics. Int. Immunopharmacol. 2021, 99, 107984. [Google Scholar] [CrossRef]
  297. Wagner, L.I.; Cella, D. Fatigue and Cancer: Causes, Prevalence and Treatment Approaches. Br. J. Cancer 2004, 91, 822–828. [Google Scholar] [CrossRef] [PubMed]
  298. Valcarcel, D.; Verma, A.; Platzbecker, U.; Santini, V.; Giagounidis, A.; Díez-Campelo, M.; Janssen, J.; Schlenk, R.F.; Gaidano, G.; Perez de Oteyza, J.; et al. Phase 2 Study of Monotherapy Galunisertib (LY2157299 Monohydrate) in Very Low-, Low-, and Intermediate-Risk Patients with Myelodysplastic Syndromes. Blood 2015, 126, 1669. [Google Scholar] [CrossRef]
  299. Niyongere, S.; Saltos, A.; Gray, J.E. Immunotherapy Combination Strategies (Non-Chemotherapy) in Non-Small Cell Lung Cancer. J. Thorac. Dis. 2018, 10 (Suppl. S3), S433–S450. [Google Scholar] [CrossRef] [PubMed]
  300. Kovacs, R.J.; Maldonado, G.; Azaro, A.; Fernández, M.S.; Romero, F.L.; Sepulveda-Sánchez, J.M.; Corretti, M.; Carducci, M.; Dolan, M.; Gueorguieva, I.; et al. Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study. Cardiovasc. Toxicol. 2015, 15, 309–323. [Google Scholar] [CrossRef]
  301. Chen, H.; Fan, L.; Peng, N.; Yin, Y.; Mu, D.; Wang, J.; Meng, R.; Xie, J. Galunisertib-Loaded Gelatin Methacryloyl Hydrogel Microneedle Patch for Cardiac Repair after Myocardial Infarction. ACS Appl. Mater. Interfaces 2022, 14, 40491–40500. [Google Scholar] [CrossRef] [PubMed]
  302. Yingling, J.M.; Blanchard, K.L.; Sawyer, J.S. Development of TGF-beta signalling inhibitors for cancer therapy. Nat. Rev. Drug Discov. 2004, 3, 1011–1022. [Google Scholar] [CrossRef]
  303. Kelley, R.K.; Gane, E.; Assenat, E.; Siebler, J.; Galle, P.R.; Merle, P.; Hourmand, I.O.; Cleverly, A.; Zhao, Y.; Gueorguieva, I.; et al. A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients with Advanced Hepatocellular Carcinoma. Clin. Transl. Gastroenterol. 2019, 10, e00056. [Google Scholar] [CrossRef]
  304. Melisi, D.; Garcia-Carbonero, R.; Macarulla, T.; Pezet, D.; Deplanque, G.; Fuchs, M.; Trojan, J.; Kozloff, M.; Simionato, F.; Cleverly, A.; et al. TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer. Cancer Chemother. Pharmacol. 2019, 83, 975–991. [Google Scholar] [CrossRef]
  305. Gonzalez-Sanchez, E.; Vaquero, J.; Férnandez-Barrena, M.G.; Lasarte, J.J.; Avila, M.A.; Sarobe, P.; Reig, M.; Calvo, M.; Fabregat, I. The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma? Cancers 2021, 13, 3248. [Google Scholar] [CrossRef]
  306. Strauss, J.; Heery, C.R.; Schlom, J.; Madan, R.A.; Cao, L.; Kang, Z.; Lamping, E.; Marté, J.L.; Donahue, R.N.; Grenga, I.; et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors. Clin. Cancer Res. 2018, 24, 1287–1295. [Google Scholar] [CrossRef]
  307. Jung, B.; Staudacher, J.J.; Beauchamp, D. Transforming Growth Factor β Superfamily Signaling in Development of Colorectal Cancer. Gastroenterology 2017, 152, 36–52. [Google Scholar] [CrossRef]
  308. Kim, B.G.; Malek, E.; Choi, S.H.; Ignatz-Hoover, J.J.; Driscoll, J.J. Novel therapies emerging in oncology to target the TGF-β pathway. J. Hematol. Oncol. 2021, 14, 55. [Google Scholar] [CrossRef]
  309. Malek, E.; Rana, P.S.; Swamydas, M.; Daunov, M.; Miyagi, M.; Murphy, E.; Ignatz-Hoover, J.J.; Metheny, L.; Kim, S.J.; Driscoll, J.J. The TGFβ Type I Receptor Kinase Inhibitor Vactosertib in Combination with Pomalidomide in Relapsed/Refractory Multiple Myeloma: A Phase 1b Trial. Nat. Commun. 2024, 15, 7388. [Google Scholar] [CrossRef]
  310. Yap, T.A.; Vieito, M.; Baldini, C.; Sepúlveda-Sánchez, J.M.; Kondo, S.; Simonelli, M.; Cosman, R.; van der Westhuizen, A.; Atkinson, V.; Carpentier, A.F.; et al. First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer. Clin. Cancer Res. 2021, 27, 6666–6676. [Google Scholar] [CrossRef]
  311. Stein, E.M.; Tallman, M.S. Emerging therapeutic drugs for AML. Blood 2016, 127, 71–78. [Google Scholar] [CrossRef] [PubMed]
  312. Nikanjam, M.; Kato, S.; Kurzrock, R. Liquid biopsy: Current technology and clinical applications. J. Hematol. Oncol. 2022, 15, 131. [Google Scholar] [CrossRef] [PubMed]
  313. Yan, H.H.N.; Chan, A.S.; Lai, F.P.; Leung, S.Y. Organoid cultures for cancer modeling. Cell Stem Cell 2023, 30, 917–937. [Google Scholar] [CrossRef] [PubMed]
  314. U.S. National Library of Medicine. Capmatinib. Available online: https://www.ncbi.nlm.nih.gov/books/NBK595111/ (accessed on 26 May 2025).
  315. BerGenBio ASA. Bemcentinib Pipeline—NSCLC and Other Indications. Available online: https://www.bergenbio.com/pipeline/bemcentinib-cornerstone-therapy-nsclc (accessed on 26 May 2025).
  316. Krebs, M.G.; Branson, A.; Barber, S.; Poile, C.; King, A.; Greystoke, A.; Moody, S.; Nolan, L.; Scotland, M.; Darlison, L.; et al. Bemcentinib and Pembrolizumab in Patients with Relapsed Mesothelioma: MIST3, a Phase IIa Trial with Cellular and Molecular Correlates of Efficacy. J. Clin. Oncol. 2023, 41 (Suppl. S16), 8511. [Google Scholar] [CrossRef]
  317. Harding, J.J.; Cloughesy, T.F.; Mellinghoff, I.K.; Wen, P.Y.; Abrey, L.E.; Ellingson, B.M.; Aldape, K.D.; Penas-Prado, M.; Kuhn, J.; Mack, F.; et al. Phase 1b Study of Galunisertib and Ramucirumab in Patients with Advanced Hepatocellular Carcinoma. Cancer Med. 2021, 10, 3059–3067. [Google Scholar] [CrossRef] [PubMed]
  318. Nadal, E.; Saleh, M.; Aix, S.P.; Ochoa-de-Olza, M.; Patel, S.P.; Antonia, S.; Zhao, Y.; Gueorguieva, I.; Man, M.; Estrem, S.T.; et al. A Phase Ib/II Study of Galunisertib in Combination with Nivolumab in Solid Tumors and Non-Small Cell Lung Cancer. BMC Cancer 2023, 23, 708. [Google Scholar] [CrossRef] [PubMed]
  319. Melisi, D.; Oh, D.Y.; Hollebecque, A.; Calvo, E.; Varghese, A.; Borazanci, E.; Macarulla, T.; Merz, V.; Zecchetto, C.; Zhao, Y.; et al. Safety and Activity of the TGFβ Receptor I Kinase Inhibitor Galunisertib Plus the Anti-PD-L1 Antibody Durvalumab in Metastatic Pancreatic Cancer. J. Immunother. Cancer 2021, 9, e002068. [Google Scholar] [CrossRef]
  320. Brazel, D.; Zhang, S.; Nagasaka, M. Spotlight on Tepotinib and Capmatinib for Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation. Lung Cancer 2022, 13, 33–45. [Google Scholar] [CrossRef]
  321. Wick, A.; Desjardins, A.; Suarez, C.; Forsyth, P.; Gueorguieva, I.; Burkholder, T.; Cleverly, A.L.; Estrem, S.T.; Wang, S.; Lahn, M.M.; et al. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma. Investig. New Drugs 2020, 38, 1570–1579. [Google Scholar] [CrossRef] [PubMed]
Jcm 14 06853 g001
Figure 1. The dynamic epithelial–mesenchymal transition spectrum, highlighting the intermediate hybrid E/M state and its key molecular regulators—including EMT transcription factors (such as SNAIL, SLUG, ZEB1/2), epigenetic modulators, and signaling pathways (such as TGF-β, MET, and AXL)—while a schematic timeline beneath maps tumor progression stages and aligns therapeutic strategies (e.g., early EMT inhibition with galunisertib and later MET targeting with capmatinib or bemcentinib) to emphasize the timing-dependent, reversible nature of EMT in cancer progression. All abbreviations employed are defined in the text in the Abbreviations section.
Figure 1. The dynamic epithelial–mesenchymal transition spectrum, highlighting the intermediate hybrid E/M state and its key molecular regulators—including EMT transcription factors (such as SNAIL, SLUG, ZEB1/2), epigenetic modulators, and signaling pathways (such as TGF-β, MET, and AXL)—while a schematic timeline beneath maps tumor progression stages and aligns therapeutic strategies (e.g., early EMT inhibition with galunisertib and later MET targeting with capmatinib or bemcentinib) to emphasize the timing-dependent, reversible nature of EMT in cancer progression. All abbreviations employed are defined in the text in the Abbreviations section.
Jcm 14 06853 g001
Jcm 14 06853 g002
Figure 2. Structural formula of capmatinib.
Figure 2. Structural formula of capmatinib.
Jcm 14 06853 g002
Jcm 14 06853 g003
Figure 3. HGF/MET pathway activation according to [141]. When hepatocyte growth factor (HGF) binds to the MET receptor, it triggers structural alterations that promote receptor dimerization and mutual phosphorylation of tyrosine residues within MET’s kinase domain, as well as phosphorylation of tyrosines in the C-terminal region. These phosphorylated sites serve as anchoring points for various adaptor proteins and kinase effectors. Activation of MET subsequently initiates downstream signaling cascades, including the MAPK, PI3K/AKT, and STAT3 pathways, which are involved in regulating cell growth, survival, movement, and invasive behavior in a MET-dependent manner. The MAPK pathway is a signaling cascade that regulates cell growth and survival. It is triggered by receptor activation and proceeds through sequential activation of RAS, RAF, MEK, and ERK. The PI3K/AKT pathway controls cell survival and metabolism. Activation of PI3K leads to the formation of PIP3, which activates AKT, promoting anti-apoptotic and growth signals. The STAT3 pathway regulates gene expression. STAT3 is phosphorylated, dimerizes, and translocates to the nucleus to activate genes involved in proliferation and survival. All abbreviations employed are defined in the text in the Abbreviations section.
Figure 3. HGF/MET pathway activation according to [141]. When hepatocyte growth factor (HGF) binds to the MET receptor, it triggers structural alterations that promote receptor dimerization and mutual phosphorylation of tyrosine residues within MET’s kinase domain, as well as phosphorylation of tyrosines in the C-terminal region. These phosphorylated sites serve as anchoring points for various adaptor proteins and kinase effectors. Activation of MET subsequently initiates downstream signaling cascades, including the MAPK, PI3K/AKT, and STAT3 pathways, which are involved in regulating cell growth, survival, movement, and invasive behavior in a MET-dependent manner. The MAPK pathway is a signaling cascade that regulates cell growth and survival. It is triggered by receptor activation and proceeds through sequential activation of RAS, RAF, MEK, and ERK. The PI3K/AKT pathway controls cell survival and metabolism. Activation of PI3K leads to the formation of PIP3, which activates AKT, promoting anti-apoptotic and growth signals. The STAT3 pathway regulates gene expression. STAT3 is phosphorylated, dimerizes, and translocates to the nucleus to activate genes involved in proliferation and survival. All abbreviations employed are defined in the text in the Abbreviations section.
Jcm 14 06853 g003
Jcm 14 06853 g004
Figure 4. Structural formula of bemcentinib.
Figure 4. Structural formula of bemcentinib.
Jcm 14 06853 g004
Jcm 14 06853 g005
Figure 5. The mechanism of action of bemcenitinib according to [238].The TAM receptor tyrosine kinase family—comprising TYRO-3, AXL, and MER—regulates key cancer-related processes such as cell growth, survival, migration, and metastasis. Among them, AXL is strongly associated with tumor progression, therapy resistance, and immune evasion. The AXL gene, located on chromosome 19q13.2 and made up of 20 exons, encodes a receptor with extracellular IgG-like and fibronectin III domains, a transmembrane region, and an intracellular kinase domain. Increased AXL expression causes resistance to therapies targeting B-RAF (B-Raf proto-oncogene, serine/threonine kinase), a gene that encodes a protein kinase involved in cell growth signaling and is often mutated in melanoma, and also diminishes the effectiveness of PD-1 blockade treatments. All abbreviations employed are defined in the text in the Abbreviations section.
Figure 5. The mechanism of action of bemcenitinib according to [238].The TAM receptor tyrosine kinase family—comprising TYRO-3, AXL, and MER—regulates key cancer-related processes such as cell growth, survival, migration, and metastasis. Among them, AXL is strongly associated with tumor progression, therapy resistance, and immune evasion. The AXL gene, located on chromosome 19q13.2 and made up of 20 exons, encodes a receptor with extracellular IgG-like and fibronectin III domains, a transmembrane region, and an intracellular kinase domain. Increased AXL expression causes resistance to therapies targeting B-RAF (B-Raf proto-oncogene, serine/threonine kinase), a gene that encodes a protein kinase involved in cell growth signaling and is often mutated in melanoma, and also diminishes the effectiveness of PD-1 blockade treatments. All abbreviations employed are defined in the text in the Abbreviations section.
Jcm 14 06853 g005
Jcm 14 06853 g006
Figure 6. Structural formula of galunisertib.
Figure 6. Structural formula of galunisertib.
Jcm 14 06853 g006
Jcm 14 06853 g007
Figure 7. Mechanism of action of galunisertib according to [305]. TGF-β is a protein that plays a crucial role in regulating cell growth, differentiation, and immune responses. In cancer, abnormal TGF-β signaling can promote tumor growth, invasion, and immune evasion. Targeting TGF-β signaling in cancer treatment involves blocking the pathway that transmits signals from the TGF-β protein to the inside of the cell. This can be done by inhibiting downstream signaling components, such as the kinase activity of the TGF-β receptor. Small molecule kinase inhibitors like galunisertib work by blocking this receptor’s activity (targeting TβRI kinase), preventing the cancer-promoting signals from being carried out. Mature TGF-β binds to type I and type II serine/threonine kinase receptors (TβRI and TβRII), forming a heterotetrameric complex. The constitutively active TβRII phosphorylates and activates TβRI, which then initiates the canonical TGF-β signaling pathway. Activated TβRI phosphorylates SMAD family of proteins: SMAD2 and SMAD3 at their C-terminal serine residues. These phosphorylated SMADs form a trimeric complex with SMAD4, translocate to the nucleus, and regulate gene expression in cooperation with other transcription factors. Beyond transcriptional regulation, SMADs influence gene expression through epigenetic changes, RNA splicing, and miRNA processing. All abbreviations employed are defined in the text in the Abbreviations section.
Figure 7. Mechanism of action of galunisertib according to [305]. TGF-β is a protein that plays a crucial role in regulating cell growth, differentiation, and immune responses. In cancer, abnormal TGF-β signaling can promote tumor growth, invasion, and immune evasion. Targeting TGF-β signaling in cancer treatment involves blocking the pathway that transmits signals from the TGF-β protein to the inside of the cell. This can be done by inhibiting downstream signaling components, such as the kinase activity of the TGF-β receptor. Small molecule kinase inhibitors like galunisertib work by blocking this receptor’s activity (targeting TβRI kinase), preventing the cancer-promoting signals from being carried out. Mature TGF-β binds to type I and type II serine/threonine kinase receptors (TβRI and TβRII), forming a heterotetrameric complex. The constitutively active TβRII phosphorylates and activates TβRI, which then initiates the canonical TGF-β signaling pathway. Activated TβRI phosphorylates SMAD family of proteins: SMAD2 and SMAD3 at their C-terminal serine residues. These phosphorylated SMADs form a trimeric complex with SMAD4, translocate to the nucleus, and regulate gene expression in cooperation with other transcription factors. Beyond transcriptional regulation, SMADs influence gene expression through epigenetic changes, RNA splicing, and miRNA processing. All abbreviations employed are defined in the text in the Abbreviations section.
Jcm 14 06853 g007
Table 1. The role of epithelial–mesenchymal transition transcription factors (EMT-TF) in tumour cell motility (TCM) according to [70]. All abbreviations employed are defined in the text in the Abbreviations section.
Table 1. The role of epithelial–mesenchymal transition transcription factors (EMT-TF) in tumour cell motility (TCM) according to [70]. All abbreviations employed are defined in the text in the Abbreviations section.
EMT-TFFamilyKey FunctionsRegulationTarget Genes & PathwaysImpact on
Cancer Biology
SNAIL1/2Zinc finger (SNAIL family)Repress epithelial genes (e.g., E-cadherin);
Suppress tight junction proteins (claudins, occludins, ZO-1, connexins);
Inhibit CRUMBS3 (affects polarity)		Activated by TGF-β, EGF, IGF-1, HGF, Wnt/β-catenin, NOTCH;
Regulated by GSK3 (degradation);
PAK1 phosphorylation (promotes nuclear localization)		E-cadherin, MMPs (context-dependent);
CRUMBS3;
Alters glucose metabolism (glycolysis shift)		Promotes stemness, invasion, therapy resistance;
Associated with poor prognosis and recurrence
TWIST1/2bHLHDownregulates E-cadherin;
Upregulates fibronectin, N-cadherin, vimentin;
Supports stemness and invasion		Regulated by TGF-β2, AKT2, PDGFR;
Enhanced by MAPK/AKT phosphorylation		E-cadherin, fibronectin, N-cadherin, vimentin;
Controls TGF-β2, AKT2, PDGFR;		Drives EMT and metastasis;
Enhances cancer motility and stem-like traits
ZEB1/2Zinc finger
(E-box-binding homeobox)		Represses epithelial genes (e.g., E-cadherin);
Activates mesenchymal genes;
Represses polarity genes (CDH1, Lgl2, PATJ, Crumbs3)		Induced by estrogen, TGF-β, Wnt/β-catenin-Modulated by SNAIL1 and TWIST1E-cadherin, MMPs, polarity genesPromotes EMT and metastasis;
Associated with therapy resistance and poor prognosis
Table 2. Selected cytoplasmic MET (cMET) inhibitor compounds and their mechanisms of action on the cMET pathway along with corresponding to each type of cMET pathway inhibition, according to [142]. All abbreviations employed are defined in the text in the Abbreviations section.
Table 2. Selected cytoplasmic MET (cMET) inhibitor compounds and their mechanisms of action on the cMET pathway along with corresponding to each type of cMET pathway inhibition, according to [142]. All abbreviations employed are defined in the text in the Abbreviations section.
Mechanism/
Inhibitor		Target/
Pathway Activity		Effect on cMET
Signaling		Clinical Relevance/
Notes
Selective cMET TKI; Direct cMET inhibition
(Capmatinib)		Inhibits cMET, GAB1, SRC, PI3K; blocks AKT, MAPKPrevents activation of downstream signalingApproved for NSCLC with MET exon 14 skipping mutations
Selective cMET inhibitor; Direct inhibition
(Savolitinib)		Inhibits cMET phosphorylation; blocks survival and proliferation pathwaysInhibits cMET downstream signalingInvestigated in NSCLC and gastric cancer
Selective cMET inhibitor; Direct inhibition
(Tepotinib)		Prevents cMET dimerization and phosphorylation; inhibits STAT3, PI3K/AKT, MAPKPrevents cMET signaling and downstream cascade activationApproved for NSCLC with MET exon 14 skipping mutations
Monoclonal antibody; HGF binding inhibitor
(Onartuzumab)		Blocks HGF binding; prevents receptor dimerization and downstream PI3K, RAS/MAPK signalingPrevents receptor activation at extracellular levelExplored in clinical trials; limited efficacy alone, combined therapies being explored
Multi-kinase inhibitor (cMET, VEGFR, AXL) (Cabozantinib)Inhibits cMET and angiogenesis pathways (VEGFR)Inhibits tumor growth via cMET and VEGFR pathwaysApproved for renal cell carcinoma and thyroid cancer
Multi-targeted TKI (cMET, VEGFR, RON)
(Foretinib)		Inhibits migration/invasion pathways (FAK, RAC1/JNK)Broad inhibition including cMET, VEGFR pathwaysEvaluated in trials for gastric and other cancers
Non-ATP competitive cMET inhibitor
(Tivantinib)		Disrupts cMET signaling; inhibits survival/proliferation; mechanism partially unclearBlocks downstream effects despite unclear kinase bindingClinical trials in lung and liver cancers
TKI; Direct cMET kinase inhibition
(Crizotinib)		Inhibits cMET autophosphorylation; blocks AKT/mTOR, RAS/RAF/MAPK, STAT3Prevents downstream signaling cascadesApproved for NSCLC with cMET alterations; also inhibits ALK
Table 3. Targeting Aberrantly Activated AXL to attenuate EMT and overcome drug resistance according to [223]. All abbreviations employed are defined in the text in the Abbreviations section.
Table 3. Targeting Aberrantly Activated AXL to attenuate EMT and overcome drug resistance according to [223]. All abbreviations employed are defined in the text in the Abbreviations section.
FeatureTargeting Aberrantly Activated AXL
Key InhibitorsBemcentinib (AXL inhibitor), Selumetinib (MEK inhibitor combo)
Primary Cell Type TargetedMesenchymal cells (AXL), epithelial cells (MEK inhibitor)
Mechanism of ActionBlocks AXL-driven EMT signaling activated by TGF-β and hypoxia
Effect on EMTAttenuates TGF-β and hypoxia-induced EMT
Impact on Drug ResistanceRestores TKI sensitivity, reduces growth of EMT and drug-resistant tumors
Combination StrategiesCombined with MEK inhibitor selumetinib for dual epithelial and mesenchymal targeting
Apoptosis InductionIndirect via EMT attenuation
Clinical ImplicationsPromising for overcoming resistance in tumors with EMT and drug resistance
ChallengesRequires targeting multiple pathways due to EMT complexity
Table 4. TGFβ pathway overview according to [247]. All abbreviations employed are defined in the text in the Abbreviations section.
Table 4. TGFβ pathway overview according to [247]. All abbreviations employed are defined in the text in the Abbreviations section.
Stage/ComponentDetails
Ligand InteractionThe function of TGFβ ligands is influenced by the variety and concentration of ligands and receptors present, alongside extracellular inhibitors and accessory molecules. Proteins like Gremlin 1 (GREM1) can suppress related signaling pathways (such as BMP), affecting cellular characteristics. Co-receptors like β-glycan and CRIPTO facilitate or hinder receptor activation based on context.
Receptor Complex FormationTGFβ receptors assemble as heterotetramers comprising type I and type II subunits, each with multiple variants. Binding of ligands prompts type II receptors to phosphorylate type I receptors, initiating downstream signaling. The specific pairing of receptor subtypes with ligands dictates the cellular response. Regulatory factors like FKBP12 and BAMBI inhibit receptor activation to fine-tune signaling output.
Canonical Intracellular SignalingActivated type I receptors phosphorylate receptor-specific SMAD proteins (R-SMADs), which combine with SMAD4 to form complexes that translocate to the nucleus. Different R-SMADs respond to TGFβ-like or BMP-like signals, while inhibitory SMADs (SMAD6/7) suppress the pathway. Scaffold proteins such as SARA regulate SMAD phosphorylation and activation.
Non-Canonical Intracellular PathwaysIn addition to SMAD-dependent signaling, TGFβ receptors engage alternative pathways including MAPK cascades (JNK, p38, ERK), PI3K-AKT signaling, and Rho GTPase activation. These non-canonical routes interact with SMAD signaling to shape cellular outcomes, though their roles depend on the specific physiological or pathological setting.
Nuclear RegulationSMAD complexes are imported into the nucleus via specialized transport proteins, where they partner with cell-specific transcription factors to control gene expression. They also recruit chromatin remodeling enzymes that either promote or repress transcription. Alternative SMAD interactions, such as with TRIM33, facilitate opening of chromatin regions critical for differentiation and development.
Table 5. Selected targeted small-molecule inhibitors of EMT pathways in cancer therapy on the examples of comparison of capmatinib, bemcentinib and galunisertib according to [314,315,316,317,318,319,320,321]. All abbreviations employed are defined in the text in the Abbreviations section.
Table 5. Selected targeted small-molecule inhibitors of EMT pathways in cancer therapy on the examples of comparison of capmatinib, bemcentinib and galunisertib according to [314,315,316,317,318,319,320,321]. All abbreviations employed are defined in the text in the Abbreviations section.
Feature/DrugCapmatinib (Tabrecta®)Bemcentinib (BGB324)Galunisertib (LY2157299)
Mechanism of ActionSelective MET tyrosine kinase inhibitor; targets MET exon 14 skipping mutationsSelective AXL receptor tyrosine kinase inhibitor; blocks EMT, metastasis, immune evasionOral inhibitor of TGF-β receptor I kinase (ALK5); suppresses TGF-β-driven EMT and immune evasion
Clinical ApplicationsApproved for metastatic NSCLC with MET exon 14 skipping mutationsNSCLC (especially STK11-mutant), AML, MMCRC/RC, HCC, GBM, MDS, NSCLC, PC
Clinical TrialsGBM (NCT02386826), NSCLC (NCT04427072, NCT01911507, NCT05435846) AML (NCT02488408, NCT03824080), MM (MiST3 NCT03654833),
NSCLC (NCT05469178, NCT03184571, NCT02424617) 		ASolT (NCT01682187), CRC (NCT05700656), HCC (NCT02240433), GBM (NCT01582269), PC (NCT02734160), PCa (NCT02452008), RC (NCT02688712)
Common Adverse EffectsPeripheral edema, nausea, fatigue, vomiting, dyspnea, elevated liver enzymes, pancreatitis, interstitial lung disease (ILD)Elevated liver enzymes, fatigue, diarrhea, anemia, thrombocytopenia, QTc prolongationFatigue, diarrhea, nausea, vomiting, constipation, transaminase elevation, cytopenias, thrombosis, neutropenia, dyspnea, hypophosphatemia, hand-foot syndrome
Regulatory StatusFDA-approved for METex14 NSCLCFast Track designation by FDA for elderly relapsed AMLInvestigational; in various phase trials for multiple cancers
EfficacyHigh in METex14-mutated NSCLC; ORR ~68% in treatment-naïve patientsModest; ORR ~46% in NSCLC with pembrolizumabVariable; improved OS in pancreatic cancer with gemcitabine
ToxicityGenerally mild; nausea, fatigue, peripheral edemaMild to moderate; rash, diarrhea, fatigue, elevated liver enzymesMild; no dose-limiting toxicities reported
ResistanceLow; rare mutations reportedModerate; common in ~20% of casesHigh; frequent relapse observed
Key Trial OutcomesImproved OS and PFS in METex14-mutated NSCLCNo significant improvement in efficacy with combination therapiesProlonged OS with gemcitabine in pancreatic cancer; minimal added toxicity
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kawczak, P.; Feszak, I.J.; Bączek, T. Targeted Therapies Modulating Mesenchymal–Epithelial Transition-Linked Oncogenic Signaling in the Tumor Microenvironment: Comparative Profiling of Capmatinib, Bemcentinib, and Galunisertib. J. Clin. Med. 2025, 14, 6853. https://doi.org/10.3390/jcm14196853

AMA Style

Kawczak P, Feszak IJ, Bączek T. Targeted Therapies Modulating Mesenchymal–Epithelial Transition-Linked Oncogenic Signaling in the Tumor Microenvironment: Comparative Profiling of Capmatinib, Bemcentinib, and Galunisertib. Journal of Clinical Medicine. 2025; 14(19):6853. https://doi.org/10.3390/jcm14196853

Chicago/Turabian Style

Kawczak, Piotr, Igor Jarosław Feszak, and Tomasz Bączek. 2025. "Targeted Therapies Modulating Mesenchymal–Epithelial Transition-Linked Oncogenic Signaling in the Tumor Microenvironment: Comparative Profiling of Capmatinib, Bemcentinib, and Galunisertib" Journal of Clinical Medicine 14, no. 19: 6853. https://doi.org/10.3390/jcm14196853

APA Style

Kawczak, P., Feszak, I. J., & Bączek, T. (2025). Targeted Therapies Modulating Mesenchymal–Epithelial Transition-Linked Oncogenic Signaling in the Tumor Microenvironment: Comparative Profiling of Capmatinib, Bemcentinib, and Galunisertib. Journal of Clinical Medicine, 14(19), 6853. https://doi.org/10.3390/jcm14196853

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop