Search Results (182)

This study aimed to investigate the tyrosine kinase inhibitor Nintedanib and its potential role in reversing epithelial–mesenchymal transition (EMT) induced by transforming growth factor beta 2 (TGF-β2) in retinal pigment epithelial (RPE) cells, along with its therapeutic potential using a mouse model of subretinal fibrosis. We hypothesized that the blockade of angiogenesis promoting and fibrosis inducing signaling using the receptor tyrosine kinase inhibitor Nintedanib (OfevTM) can prevent or reverse EMT both in vitro and in our in vivo model of subretinal fibrosis. Primary human retinal pigment epithelial cells (phRPE) and adult retinal pigment epithelial cell line (ARPE-19) cells were treated with TGF-β210 ng/mL for two days followed by four days of Nintedanib (1 µM) incubation. Epithelial and mesenchymal phenotypes were assessed by morphological examination, quantitative real-time polymerase chain reaction(qPCR) (ZO-1, Acta2, FN, and Vim), and immunocytochemistry (ZO-1, vimentin, fibronectin, and αSMA). Metabolites were measured using luciferase-based assays. Extracellular acidification and oxygen consumption rates were measured using the Seahorse XF system. Metabolic-related genes (GLUT1, HK2, PFKFB3, CS, LDHA, LDHB) were evaluated by qPCR. A model of subretinal fibrosis using the two-stage laser-induced method in C57BL/6J mice assessed Nintedanib’s therapeutic potential. Fibro-vascular lesions were examined 10 days later via fluorescence angiography and immunohistochemistry. Both primary and ARPE-19 RPE stimulated with TGF-β2 upregulated expression of fibronectin, αSMA, and vimentin, and downregulation of ZO-1, consistent with morphological changes (i.e., elongation). Glucose consumption, lactate production, and glycolytic reserve were significantly increased in TGF-β2-treated cells, with upregulation of glycolysis-related genes (GLUT1, HK2, PFKFB3, CS). Nintedanib treatment reversed TGF-β2-induced EMT signatures, down-regulated glycolytic-related genes, and normalized glycolysis. Nintedanib intravitreal injection significantly reduced collagen-1+ fibrotic lesion size and Isolectin B4+ neovascularization and reduced vascular leakage in the two-stage laser-induced model of subretinal fibrosis. Nintedanib can induce Mesenchymal-to-Epithelial Transition (MET) in RPE cells and reduce subretinal fibrosis through metabolic reprogramming. Nintedanib can therefore potentially be repurposed to treat retinal fibrosis. Full article

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives. Full article

Hereditary papillary renal carcinoma (HPRC) is a rare monogenic hereditary disease in the group of hereditary cancer syndromes. Clinically, HPRC results in the development of multiple papillary renal cell carcinomas of the kidneys in young adults. HPRC is caused by point activating mutations in the MET gene encoding a transmembrane tyrosine kinase receptor. Until now, all detected germline mutations in HPRC patients were missense variants leading to a constitutive activation of the tyrosine kinase domain. We describe, for the first time, unrelated patients with clinical features similar to HPRC and without MET pathogenic missense variants but harboring an extended heterozygous duplication ~101.4 kb in length (chr7:116740252-116841718) in 7q31.2 determined using whole-genome sequencing (WGS). This duplication results in an additional copy of the MET gene fragment, including exons 5-21. The duplicated exons encode most of the receptor domains. According to the American College of Medical Genetics and Genomics (ACMG) criteria, this duplication is classified as variant of uncertain significance (VUS) at present, but it is not excluded that this duplication may represent an activating mutation. Perhaps, further segregation analysis and functional studies will allow us to more accurately resolve the pathogenicity and diagnostic significance of this germline CNV. Full article

Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive pediatric soft-tissue sarcoma driven by PAX3/7-FOXO1 fusion proteins. Despite intensive multimodal therapy, outcomes remain poor for patients with fusion-positive ARMS. This review integrates recent advances in the molecular pathogenesis of ARMS, highlighting key diagnostic and therapeutic targets. We discuss the central role of fusion proteins in transcriptional reprogramming, impaired myogenic differentiation, and super-enhancer activation. Emerging biomarkers (YAP, TFAP2B, P-cadherin) and oncogenic kinases (Aurora A, CDK4, PLK1) are evaluated alongside receptor tyrosine kinases (FGFR, MET) and transcription factors involved in metabolic rewiring (FOXF1, ETS1). Additionally, we examine immunotherapeutic strategies, epigenetic modifiers, and noncoding RNAs as potential therapeutic avenues. Together, these insights provide a comprehensive framework for developing biomarker-guided, multi-targeted therapies to improve outcomes in ARMS. Full article

Background: Recent research has increasingly highlighted alterations in the proto-oncogene MET, whose abnormal activation has been implicated in multiple cancers. MET encodes c-MET, a receptor tyrosine kinase critical for cellular growth, survival, and migration. Aberrant c-MET signaling, driven by mutations or gene amplification, promotes proliferation and invasion, contributing to tumorigenesis. Scope of the Review: While MET mutations are most often observed in non-small cell lung cancer (NSCLC), they also occur in other malignancies, including breast and gastric cancers. This review highlights key MET alterations, such as gene amplification, gene fusions, and exon 14 skipping deletions, and examines their prevalence across various tumor types. Major Conclusions: We discuss the clinical significance of c-MET as a therapeutic target and identify gaps in knowledge that could inform the development of alternative treatment strategies. Full article

Non-small-cell lung cancer (NSCLC) represents the most common type of lung cancer. The majority of patients with lung cancer characterized by activating mutations in the epidermal growth factor receptor (EGFR), benefit from therapies entailing tyrosine kinase inhibitors (TKIs). In this regard, osimertinib, a third-generation EGFR TKI, has greatly improved the outcome for patients with EGFR-mutated lung cancer. The AURA and FLAURA trials displayed the superiority of the third-generation TKI in both first- and second-line settings, making it the drug of choice for treating patients with EGFR-mutated lung cancer. Unfortunately, the onset of resistance is almost inevitable. On-target mechanisms of resistance include new mutations (e.g., C797S) in the kinase domain of EGFR, while among the off-target mechanisms, amplification of MET or HER2, mutations in downstream signaling molecules, oncogenic fusions, and phenotypic changes (e.g., EMT) have been described. This review focuses on the strategies that are currently being investigated, in preclinical and clinical settings, to overcome resistance to osimertinib, including the use of fourth-generation TKIs, PROTACs, bispecific antibodies, and ADCs, as monotherapy and as part of combination therapies. Full article

Fibroblast growth factor receptor 1 (FGFR1), also known as KAL2, is a tyrosine kinase receptor, and variants of FGFR1 have been detected in patients with Kallmann syndrome (KS), which is a congenital developmental disorder characterized by central hypogonadism and anosmia. Herein, we report an adult case of KS with a novel variant of FGFR1. A middle-aged male was referred for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup using pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on the downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa cells. It was revealed that the transfection of the variant gene significantly impaired FGFR1 signaling, detected through the downregulation of SPRY2, compared with that of the case of the forced expression of wild-type FGFR1, and that the existence of the variant gene apparently altered the expression of key steroidogenic factors, including StAR and aromatase, in the gonad. The results suggested that the novel variant of FGFR1 detected in the patient with KS was linked to the impairment of FGFR1 signaling, as well as the alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism. Full article

Osimertinib has been the standard treatment for advanced Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) for many years. However, even with remarkable response rate, progression-free survival (PFS) and survival benefit as compared to the old generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, treatment outcomes for these subsets of patients remain a challenge. Recently, in order to go beyond osimertinib, new treatment strategies have been developed. In particular, in the FLAURA 2 phase III randomized trial, the combination of platin-based chemotherapy and osimertinib showed impressive PFS benefits as compared to single-agent osimertinib. Furthermore, in the MARIPOSA phase III randomized study, the combination of the anti-EGFR and anti-MET monoclonal antibody amivantamab combined with the new anti-EGFR TKI lazertinib demonstrated remarkable PFS benefit as compared to single agent osimertinib. This paper will discuss these new treatment options and potential selection criteria for personalized treatment of patients. Full article

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with epidermal growth factor receptor (EGFR) mutations present in a substantial proportion of patients. Third-generation EGFR tyrosine kinase inhibitors (EGFR TKI), exemplified by osimertinib, have dramatically improved outcomes by effectively targeting the T790M mutation—a primary driver of acquired resistance to earlier-generation EGFR TKI. Despite these successes, resistance to third-generation EGFR TKIs inevitably emerges. Mechanisms include on-target mutations such as C797S, activation of alternative pathways like MET amplification, histologic transformations, and intricate tumor microenvironment (TME) alterations. These resistance pathways are compounded by challenges in tolerability, adverse events, and tumor heterogeneity. In light of these hurdles, this review examines the evolving landscape of combination therapies designed to enhance or prolong the effectiveness of third-generation EGFR TKIs. We explore key strategies that pair osimertinib with radiotherapy, anti-angiogenic agents, immune checkpoint inhibitors, and other molecularly targeted drugs, and we discuss the biological rationale, preclinical evidence, and clinical trial data supporting these approaches. Emphasis is placed on how these combinations may circumvent diverse resistance mechanisms, improve survival, and maintain a favorable safety profile. By integrating the latest findings, this review aims to guide clinicians and researchers toward more individualized and durable treatment options, ultimately enhancing both survival and quality of life for patients with EGFR-mutated NSCLC. Full article

Background/Objectives: Colorectal cancer (CRC) is the third most common cancer in the US and the second leading cancer-associated mortality cause. Available CRC therapies achieve modest outcomes and fail to prevent its recurrence. Epidemiological studies indicated that the Mediterranean diet rich in olive oil reduced CRC incidence. This study aimed at the identification and assessment of active anti-CRC olive phenolics. Methods: The MTT, wound-healing and colony formation assays were used to discover and assess the in vitro anti-CRC activity of olive phenolics. A nude mouse xenografting model was used to assess the in vivo CRC progression and recurrence suppressive activity of OC in pure and crude forms. OC was isolated from olive oil using liquid–liquid extractions. Results: Screening of olive phenolics for in vitro antiproliferative activity against a diverse panel of CRC cell lines identified the extra-virgin olive oil (EVOO) S-(-)-oleocanthal (OC) as the most active hit. OC showed IC₅₀ values of 4.2, 9.8, 14.5, and 4.9 μM against HCT-116, COLO-320DM, WiDr, and SW48 CRC cells, respectively. The lysine methyltransferases SMYD2 and EZH2, along with the receptor tyrosine kinase c-MET proved aberrantly dysregulated in invasive and metastatic CRC. SMYD2 and c-MET were validated as OC molecular targets in multiple malignancies. Daily oral 10 mg/kg OC treatments over 15 days suppressed 72.5% of the KRAS mutant HCT-116-Luc cells tumors weight in male nude mice. Continued OC daily oral use after primary tumor surgical excision over an additional 40 days significantly suppressed the HCT-116-Luc locoregional tumor recurrence and totally prevented the distant tumor recurrence. The SMYD2-EZH2 expressions and c-MET activation were notably suppressed by OC treatments in vitro and in collected animal primary tumors. Conclusions: OC and olive phenolics are potential nutraceutical interventions useful for CRC control and the prevention of its relapse. Full article

The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that mediates the activity of a variety of downstream pathways upon its activation. These pathways regulate various physiological processes within the cell, including growth, survival, proliferation, and motility. Under normal physiological conditions, this allows MET to regulate various development and regenerative processes; however, mutations resulting in aberrant MET activity and the consequent dysregulation of downstream signaling can contribute to cellular pathophysiology. Mutations within MET have been identified in a variety of cancers and have been shown to mediate tumorigenesis by increasing RTK activity and downstream signaling. In lung cancer specifically, a number of patients have been identified as possessing MET alterations, commonly receptor amplification (METamp) or splice site mutations resulting in loss of exon 14 (METex14). Due to MET’s role in mediating oncogenesis, it has become an attractive clinical target and has led to the development of various targeted therapies, including MET tyrosine kinase inhibitors (TKIs). Unfortunately, these TKIs have demonstrated limited clinical efficacy, as patients often present with either primary or acquired resistance to these therapies. Mechanisms of resistance vary but often occur through off-target or bypass mechanisms that render downstream signaling pathways insensitive to MET inhibition. This review provides an overview of the therapeutic landscape for MET-positive cancers and explores the various mechanisms that contribute to therapeutic resistance in these cases. Full article

The MET oncogene, encoding the hepatocyte growth factor (HGF) receptor, plays a key role in tumorigenesis, invasion, and resistance to therapy, yet its full biological functions and activation mechanisms remain incompletely understood. A feature of MET is its extensive interaction network, encompassing the following: (i) receptor tyrosine kinases (RTKs); (ii) co-receptors (e.g., CDCP1, Neuropilin1); (iii) adhesion molecules (e.g., integrins, tetraspanins); (iv) proteases (e.g., ADAM10); and (v) other receptors (e.g., CD44, plexins, GPCRs, and NMDAR). These interactions dynamically modulate MET’s activation, signaling, intracellular trafficking, and degradation, enhancing its functional versatility and oncogenic potential. This review offers current knowledge on MET’s partnerships, focusing on their functional impact on signaling output, therapeutic resistance, and cellular behavior. Finally, we evaluate emerging combination therapies targeting MET and its interactors, highlighting their potential to overcome resistance and improve clinical outcomes. By exploring the complex interplay within the MET network of interacting cell surface proteins, this review provides insights into advancing anti-cancer strategies and understanding the broader implications of RTK crosstalk in oncology. Full article

Cancer is a significant global health challenge, comprising over 200 distinct types that severely impact life expectancy and account for high mortality rates in the 21st century. This complexity underscores the urgent need for ongoing research, preventive strategies, and improved treatment options. In the quest for new anticancer drug candidates, arylnaphthalene lignan lactones—natural compounds found in plants like Phyllanthus and Cleistanthus—have gained attention due to their antioxidant, anti-inflammatory, and anticancer properties. An in silico study was conducted to evaluate their potential against colon cancer by targeting epidermal growth factor receptor (EGFR), a key tyrosine kinase. Docking simulations revealed that these compounds exhibited excellent stability within the active site of EGFR, with docking scores of −8.02 and −7.96 kcal/mol. Further, the derivatives demonstrated significant interactions, including hydrogen bonds with Met 769 and hydrophobic contacts within the EGFR cavity, akin to those formed by the known inhibitor 4-anilinoquinazoline. An ADMET analysis was also performed to evaluate their pharmacokinetic properties and toxicity, further supporting their potential as promising anticancer agents. Full article

Although rare, Merkel cell carcinoma (MCC) is a highly aggressive and increasingly prevalent neuroendocrine cancer of the skin. While current interventions, including surgical resection, radiation, and immunotherapy have been employed in treating many patients, those who remain unresponsive to treatment are met with sparse alternatives and a grim prognosis. For this reason, it is of interest to expand the repertoire of available therapies for MCC patients who remain resistant to current primary interventions. Recently, our improved mechanistic understanding of aberrant cell signaling observed in both MCPyV-positive and -negative MCC has facilitated exploration into several small molecules and inhibitors, among them receptor tyrosine kinase inhibitors (TKIs) and somatostatin analogs (SSAs), both of which have positively improved response rates and reduced tumor volumes upon application to treatment of MCC. The introduction of such targeted therapies into treatment protocols holds promise for more personalized care tailored towards patients of diverse subtypes, thereby improving outcomes and mitigating tumor burden, especially for treatment-resistant individuals. In this review, we characterize recent findings surrounding targeted treatments that have been applied to MCC and provide an overview of emerging perspectives on translatable options that can be further developed to offer additional therapeutic avenues for patients with the disease. Full article

Background: Dysregulation of receptor tyrosine kinase c-MET is known to promote tumor development by stimulating oncogenic signaling pathways in different cancers, including pediatric neuroblastoma (NB). NB is an extracranial solid pediatric cancer that accounts for almost 15% of all pediatric cancer-related deaths, with less than a 50% long-term survival rate. Results: In this study, we analyzed a large cohort of primary NB patient data and revealed that high MET expression strongly correlates with poor overall survival, disease progression, relapse, and high MYCN levels in NB patients. To determine the effects of c-MET in NB, we repurposed a small molecule inhibitor, tivantinib, and found that c-MET inhibition significantly inhibits NB cellular growth. Tivantinib significantly blocks NB cell proliferation and 3D spheroid tumor formation and growth in different MYCN-amplified and MYCN-non-amplified NB cell lines. Furthermore, tivantinib blocks the cell cycle at the G2/M phase transition and induces apoptosis in different NB cell lines. As expected, c-MET inhibition by tivantinib inhibits the expression of multiple genes in PI3K, STAT, and Ras cell signaling pathways. Conclusions: Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers. Full article