Search Results (2,467)

Squamous cell carcinoma of the anal canal (SCAC) is a rare malignancy whose incidence has been steadily increasing worldwide. Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16 and HPV18 genotypes, is the main etiological factor and plays a central role in tumor development. While combined chemoradiotherapy remains the standard treatment for localized disease and achieves high rates of tumor control, a considerable proportion of patients experience recurrence or present with advanced disease. For the latter, therapeutic options remain limited. Over the last decade, advances in genomic profiling have significantly expanded our understanding of SCAC biology. Recurrent alterations affecting the PI3K/AKT/mTOR pathway, especially PIK3CA mutations, have emerged as the most common molecular events, particularly in HPV-positive tumors. Additional alterations involve receptor tyrosine kinase signaling, chromatin remodeling genes, DNA damage response pathways, and components of the MAPK cascade. Moreover, HPV-positive and HPV-negative tumors display distinct molecular features with important prognostic implications. Immunotherapy has recently become an important component of treatment for advanced SCAC, although reliable predictive biomarkers are still lacking. This review summarizes the current evidence on the molecular landscape of SCAC, discusses emerging prognostic and predictive biomarkers, and highlights potential opportunities for the development of more personalized therapeutic strategies. Full article

Sorafenib is widely used to treat metastatic renal cell carcinoma (RCC); however, the acquired drug resistance limits its efficacy and application in clinical practice. The receptor tyrosine kinases c-Met and AXL play important roles in cancer progression and are involved in tyrosine kinase inhibitor-induced drug resistance in cancers, but whether these two receptors also contribute to sorafenib-induced drug resistance in RCC is unclear. In this study, we evaluated our synthesized compound 1D228, a TKI derived from Tepotinib, in sorafenib-resistant RCC models, which demonstrated further inhibition in sorafenib-resistant RCC cells, and induced 25% more reduction in resistant RCC tumor size by 1D228 combined with sorafenib compared with sorafenib monotherapy in animal models. Mechanistically, resistant RCC exhibited elevated phosphorylation of c-Met and AXL, which was effectively suppressed by 1D228. These findings indicated that compound 1D228 sensitized the sorafenib resistance of RCC by dual targeting the c-Met and AXL signaling pathways. This study suggests that 1D228 may represent a promising preclinical therapeutic strategy for RCC patients with sorafenib resistance mediated by c-Met and AXL activation. Full article

Indolo[2,3-b]quinoxalines, along with their N-substituted derivatives, exhibit pronounced anticancer activity, although the mechanisms of their biological action may vary. Herein, a panel of sixty-five 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives comprising eight series with distinct amine moieties connected to the tetracyclic indoloquinoxaline core via a dimethylene linker was evaluated as drug-like candidates for kinase binding and cytotoxic activity. The ADME (Absorption, Distribution, Metabolism, and Excretion) properties of the compounds included in this set were preliminarily determined using the SwissADME tool. Analysis revealed that the library of quinoxaline derivatives largely complies with the drug-likeness rule for kinase-targeted compounds. As part of the biological screening, the compounds were initially tested on two cell lines MonoMac-6 and THP-1 (both derived from patients with acute monocytic leukemia) using sunitinib, a known antitumor agent acting as a multi-target receptor tyrosine kinase inhibitor, as a reference compound. Compound 3g, which demonstrated the highest activity in the cytotoxicity analysis (IC₅₀ = 1.9 and 3.5 μM for the MonoMac-6 and THP-1 cell lines, respectively), was screened using the Eurofins DiscoverX scanEDGE panel, comprising 97 distinct kinases representing all known kinase families. Subsequently, the compound was tested using the Eurofins DiscoverX scanTK™ panel, covering 135 distinct receptor and non-receptor tyrosine kinases. Based on initial screening results, compound 3g exhibits relatively high binding activity against fourteen tyrosine kinases, including TYK2, ZAP70, eight mutant forms of ABL1, two mutant forms of FLT3, and one mutant form of ALK, and demonstrates relatively high binding selectivity with respect to non-mutant tyrosine kinases (S-score: 0.024). Secondary screening of nine selected analogs of compound 3g led to the identification of compound 3h, which demonstrates relatively high binding affinity for FLT3 (D835V) (K_d = 0.41 μM). Molecular modeling suggested modes of binding interaction of the compounds 3h and 3g in the FLT3 (D835V) catalytic site. Our results demonstrate that 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives could be potential candidates for developing anticancer drugs. Full article

Fms-related receptor tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations occur in approximately 20–25% of patients with acute myeloid leukemia (AML) and are associated with increased relapse risk and inferior survival outcomes. Although measurable residual disease (MRD) has become a key prognostic tool for guiding post-remission treatment decisions, FLT3-ITD was historically considered a suboptimal MRD marker because of its subclonal nature, structural heterogeneity and dynamic behavior during disease evolution. In addition, FLT3-ITD has not yet been fully integrated into routine MRD monitoring due to methodological limitations and a lack of standardized workflows. The latest European LeukemiaNet (ELN)-DAVID 2025 recommendations stressed the use of ultra-high sensitivity (UHS) next-generation sequencing (NGS) technologies to detect FLT3-ITD MRD with improved precision, enabling reliable longitudinal tracking of patient-specific clones at very low variant allele frequencies (VAF). Indeed, despite prospective evidence supporting this approach remaining limited, FLT3-ITD-based MRD monitoring is emerging as a clinically relevant prognostic indicator, contributing to the identification of patients at increased risk of relapse and refining risk stratification, while also informing therapeutic decision-making, particularly in the peri-transplant setting. The present review summarizes the biological underpinnings of FLT3-ITD mutated (FLT3-ITD^mut) AML, discusses the methodological challenges of MRD detection, and critically evaluates the evolving role of MRD in refining relapse prediction, supporting post-remission therapy tailoring, and contributing to a harmonized framework for FLT3-ITD^mut AML management. Full article

Primary bone sarcomas are rare, heterogeneous malignancies with limited therapeutic options, particularly in metastatic disease where outcomes remain poor. This study synthesizes current literature to evaluate emerging therapeutic strategies and biological determinants of response across osteosarcoma, Ewing sarcoma, and chondrosarcoma, as presented at the ESMO Annual Meeting, 2025. Key approaches reviewed include VEGFR-targeted tyrosine kinase inhibitors (TKIs), DNA damage response (DDR) inhibition, MYC targeting, immune checkpoint inhibitors (ICIs), and surfaceome-directed therapies such as antibody–drug conjugates (ADCs) and chimeric antigen receptor T cell therapy. Across studies, TKIs demonstrated short lasting activity as monotherapy but improved outcomes in some of the studies when combined with ICIs or chemotherapy, reflecting their role in remodeling the tumor microenvironment (TME); importantly, controlled studies with TKI and chemotherapy upfront are ongoing. DDR- and MYC-targeted therapies have shown strong preclinical rationale but limited clinical efficacy, highlighting challenges in translation. Immune-based therapies exhibited variable responses, with dedifferentiated chondrosarcoma (DDCS) emerging as a responsive histotype. Surfaceome-targeting strategies, particularly ADCs, demonstrated promising early clinical activity. Overall, bone sarcoma rarity, tumor heterogeneity, immunosuppressive TME, and lack of predictive factors challenge drug discovery for bone sarcoma patients. These findings underscore the importance of combination strategies and biomarker-driven patient selection and suggest that continued integration of targeted and immunotherapeutic approaches will be critical to improving outcomes in bone sarcoma. Full article

Breast cancer remains a major global health burden. Dactylospongia species have been explored for their cytotoxic potential. This study aims to evaluate the cytotoxic potential of compounds derived from the marine sponge Dactylospongia elegans. Dactylospongia elegans were collected from the Lembeh Strait, macerated using methanol, then partitioned to an ethyl acetate fraction. The cytotoxic activity of these fractions was assessed using MDA-MB-231 cells while toxicity testing was done using the BSLT. TLC was carried out to determine the groups of compounds, while LC-MS/MS was used to predict active compounds contained in the ethyl acetate fractions. In silico studies were conducted as preliminary studies to determine the antitumor mechanism. The ethyl acetate fraction and F4 subfraction of Dactylospongia elegans exhibited cytotoxicity toward MDA-MB-231 cells with IC₅₀ values of 15.72 and 41.76 µg/mL, respectively. The BSLT indicated the strongest toxicity belongs to the F6 subfraction (LC₅₀ = 32.831 µg/mL). TLC analysis confirmed the presence of major secondary metabolites as terpenoids, steroids, and alkaloids, then confirmed with LC-MS/MS including 5-epi-illimaquinone and calciferol. Molecular docking revealed that calciferol exhibited the strongest binding affinity toward tyrosine kinase and p53–MDM2 receptors, with binding energies of −10.13 and −10.28 kcal/mol, respectively. These findings suggest that Dactylospongia elegans contains bioactive constituents with potential anticancer activity, particularly against TNBC. Full article

Cardiovascular complications increasingly challenge survivors of urological cancers, given the cardiotoxicity of therapies such as androgen deprivation, vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and chemotherapy. This narrative review addresses the complex crosstalk between urological cancer treatment and cardiovascular disease. It summarizes cardiovascular toxicities linked to major antineoplastic agents, explores underlying mechanisms including metabolic and immune-mediated effects, and proposes strategies for surveillance, diagnosis, and management. Highlighting the need for multidisciplinary collaboration, it outlines future directions for research to optimize cardiovascular outcomes in this high-risk population. The increasing complexity of cardiovascular care in patients with urological malignancies highlights the need for closer collaboration between cardiologists, urologists, and oncologists, with uro-cardio-oncology emerging as an important multidisciplinary field. Full article

Modeling the dynamics of three tumor cell populations, i.e., sensitive, persister, and resistant tumor cells, during molecularly targeted therapy with tyrosine kinase inhibitors (TKIs) would be valuable for adjusting treatment plans for patients with epidermal growth factor receptor-mutated non-small cell lung cancer (EGFR-mt NSCLC). We hypothesized the time-variant tumor growth trajectories (TGTs) of patients with stage IV EGFR-mt NSCLC for the three tumor cell populations could be expressed using differential models after several follow-up computed tomography examinations. We aimed to propose differential models for TGTs in three cell populations from patients with EGFR-mt NSCLC treated with an EGFR-TKI (osimertinib). We selected two differential equations—Bertalanffy–Pütter (BP) and Gompertz—to develop TGT models. The parameters of the models were optimized based on a dual annealing method within parameter ranges determined using synthetic patient data. Using CT examinations that were not employed for model fitting, the mean absolute percentage errors (MAPEs) for BP-based and Gompertz-based models were 36.1 ± 40.2% and 43.9 ± 60.1%, respectively, for three follow-up computed tomography (FCT) examinations, which indicated no statistically significant difference (p = 0.61). This study suggests that the proposed BP-based and Gompertz-based differential models could have the potential to express TGTs in patients with stage IV EGFR-mt NSCLC treated with EGFR-TKIs after three follow-up CT examinations, although MAPEs should be mitigated in future works. Full article

Background: Anaplastic Lymphoma Kinase (ALK) is an oncogenic receptor tyrosine kinase implicated in several cancers. Despite the clinical success of ALK inhibitors, acquired resistance continues to drive the search for novel chemotypes. We developed a multiclass machine learning framework to classify ALK inhibitory activity using a curated ChEMBL dataset. Methods: Models were built using 2D molecular descriptors together with MACCS and ECFP4 fingerprints. Three widely used algorithms, Support Vector Machine (SVM), Random Forest (RF), and XGBoost, were applied for model development. Results: RF and XGBoost models demonstrated the best performance, achieving accuracies of ~0.75–0.79 with consistently high ROC–AUC values, particularly for fingerprint-based features. Bemis–Murcko scaffold analysis identified enriched chemotypes and underexplored scaffolds for further prioritization. The validated models were subsequently used to screen the Maybridge library, and compounds predicted to possess potential ALK inhibitory activity were prioritized for further computational evaluation. Applicability-domain filtering confirmed that the selected compounds occupied the predicted ALK inhibitor chemical space across multiple activity classes. The shortlisted compounds were subsequently evaluated by molecular docking to characterize their binding modes and interactions. Three candidate hits (SCR00078, SCR00073, and AW01085) were selected for further evaluation using 500 ns molecular dynamics simulations alongside the reference inhibitor Brigatinib. Simulation analyses revealed stable protein–ligand complexes and reduced conformational fluctuations relative to apo ALK, while MM/PBSA calculations identified SCR00078 and AW01085 as the most favorable binders. Conclusions: This integrated ML-to-simulation workflow prioritizes structurally novel candidate hits with predicted ALK inhibitory activity and provides an effective strategy for scaffold discovery and hit prioritization. Full article

Chronic spontaneous urticaria (CSU) is a mast cell-driven disorder defined by recurrent wheals, angioedema, or both, persisting for longer than six weeks without an identifiable external trigger. Second-generation H1-antihistamines remain first-line therapy, yet a large share of patients stay symptomatic after the dose is raised up to fourfold, and for more than a decade, omalizumab was the only targeted option for those who failed antihistamines. This began to change in 2025, when the interleukin-4 receptor alpha (IL-4Rα) antagonist dupilumab and the oral, covalent Bruton tyrosine kinase (BTK) inhibitor remibrutinib were approved for antihistamine-refractory CSU within months of one another, while the anti-KIT monoclonal antibody barzolvolimab, which depletes mast cells, advanced into the largest phase 3 program the disease has seen. This narrative review outlines the guideline framework that still anchors CSU care, appraises the pivotal efficacy and safety data for omalizumab, dupilumab, remibrutinib, and barzolvolimab, and considers how these mechanistically distinct agents might be positioned and sequenced. The widening choice makes individualized, mechanism-informed treatment a realistic goal, but it also sharpens unresolved questions about patient selection, optimal treatment duration in a naturally remitting disease, and the long-term safety of newer oral and mast cell-depleting approaches. Full article

Kinases are highly explored drug targets due to their central role in cell growth, differentiation, and cell death, as well as their relationship to cancer initiation and progression. However, with more than 500 kinases in the human kinome and significant structural similarities among them, kinases present a major selectivity challenge. Bruton’s tyrosine kinase (BTK), a highly studied kinase, plays an important role in the B-cell receptor pathway. Overexpression of BTK in B cells has been linked to the development of B-cell lymphomas, like chronic lymphocytic leukemia (CLL), as well as certain autoimmune diseases. For this reason, BTK is an attractive therapeutic target. In this review, we will provide a summary of the design of irreversible inhibitors, reversible inhibitors, and Proteolysis-targeting chimera (PROTAC) degraders targeting BTK. We will include crystal structures of compounds bound to BTK^WT and provide a review of how the design of these inhibitors and PROTACs leads to a more selective inhibition and degradation of BTK. With the emergence of identified BTK resistance mutations, alternative strategies beyond established BTK inhibitors are fundamental for designing more selective inhibitors and degraders that can overcome resistance. Full article

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs. Full article

Background: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major challenge in the treatment of EGFR-mutant lung adenocarcinoma. Identifying biomarkers associated with resistance may improve understanding of the underlying molecular mechanisms. Objective: This study aimed to identify candidate biomarkers associated with EGFR-TKI resistance using integrated bioinformatics analysis and RT-qPCR validation. Methods: Two Gene Expression Omnibus (GEO) datasets (GSE123066 and GSE178755) were analysed to identify differentially expressed genes (DEGs). Overlapping DEGs were subjected to protein–protein interaction (PPI) network construction, Gene Ontology (GO), KEGG pathway enrichment, and Kaplan–Meier survival analyses. Selected candidate genes were subsequently validated by RT-qPCR in an independent clinical cohort. Results: A total of 76 overlapping DEGs were identified, including 52 upregulated genes enriched in cell proliferation, hypoxia response, EGFR signalling, and metabolic processes. KEGG analysis identified the PI3K–Akt signalling pathway as significantly enriched. Kaplan–Meier analysis showed that higher expression of TGFA, DDIT4, and SOX9 was associated with shorter progression-free survival. RT-qPCR validation demonstrated significantly increased SOX9 expression in the resistant group, whereas TGFA and DDIT4 showed no statistically significant differences. Conclusions: Integrated bioinformatics analysis identified TGFA, DDIT4, and SOX9 as candidate genes associated with EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma. These findings provide a basis for further investigation of resistance-associated biomarkers, although larger independent cohorts and functional studies are required before clinical application. Full article

Colorectal cancer (CRC) remains a major cause of cancer mortality worldwide, highlighting the need for novel molecular targets and alternative therapeutic strategies. TYRO3, a member of the TAM receptor tyrosine kinase family, has been associated with tumor progression and poor prognosis in CRC. In this study, the effects of the natural compounds Meleagrin and Cucurbitacin B on TYRO3 expression and CRC cell behavior were investigated in HCT-116 and HT-29 cells. Cell proliferation, apoptosis, migration, and TYRO3 expression were evaluated using functional and expression-based analyses. Both compounds modulated TYRO3 expression and suppressed proliferation and wound closure dynamics in CRC cells. Cucurbitacin B exerted more pronounced antiproliferative and pro-apoptotic effects, whereas Meleagrin demonstrated antiproliferative activity with comparatively lower effects on normal colon epithelial cells (CCD 841 CoN), suggesting a potentially more favorable selectivity profile. Collectively, these findings support further mechanistic investigation of TYRO3-modulating natural compounds as potential therapeutic candidates for CRC. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, with poor survival driven by late presentation, aggressive tumor biology, and limited responsiveness to conventional systemic therapy. Advances in molecular profiling have expanded opportunities for biomarker-guided and targeted therapeutic approaches. Methods: A literature review was conducted using PubMed and the Cochrane Library through July 2026, supplemented by abstracts and proceedings from major international oncology conferences. Results: Pancreatic cancer is driven mainly by somatic changes in KRAS, TP53, CDKN2A, and SMAD4. Established precision approaches include maintenance olaparib for selected platinum-sensitive tumors with germline BRCA1 or BRCA2 pathogenic variants, immune checkpoint inhibition for mismatch repair-deficient or microsatellite instability-high tumors, and tropomyosin receptor kinase inhibition for cancers with neurotrophic tyrosine receptor kinase gene fusions. Direct inhibition of KRAS and RAS represents a major therapeutic breakthrough. KRAS G12C inhibitors established proof of concept, while agents targeting the more common KRAS G12D mutation are showing encouraging early activity. In the randomized phase III RASolute 302 trial, the multiselective RAS inhibitor daraxonrasib improved survival compared with chemotherapy in previously treated metastatic disease with oncogenic RAS mutations. Early studies of zoldonrasib combinations have extended this progress to KRAS G12D-mutant disease, although confirmation is required. Molecular profiling, next-generation sequencing, patient-derived organoids, and circulating tumor DNA may further improve treatment selection and monitoring. Conclusions: Precision oncology is becoming clinically relevant in pancreatic ductal adenocarcinoma. KRAS- and RAS-directed therapies are central advances, but resistance, toxicity, limited durability, and access to comprehensive testing remain important challenges. Full article