Search Results (136)

Although papillary thyroid carcinoma (PTC) is widely considered an immunologically cold tumor, detectable T-cell infiltration can influence disease progression in selected patients. Previous bulk analyses have linked cAMP-responsive element modulator (CREM) expression to a favorable progression-free interval and an inverse correlation with regulatory T-cell infiltration but have not resolved the cellular origin or functional state. In this study, we integrate single-cell RNA-sequencing data from a 23-sample PTC atlas with bulk Cancer Genome Atlas Thyroid Carcinoma (TCGA–THCA) validation. We show that CREM marks a T-cell receptor (TCR)-driven immediate early gene activation state in tumor-infiltrating T cells rather than a cAMP program; this state is consistently and modestly enriched within the FOXP3⁺ regulatory T-cell compartment, challenging the interpretation that bulk inverse Treg–CREM correlations reflect Treg-intrinsic repression. CREM-high T cells upregulate ANXA1, and permutation-controlled analysis identifies a candidate paracrine axis from CD4/CD8 T cells to the epithelial epidermal growth factor receptor (EGFR). At the bulk level, CREM expression correlates with reduced proliferation programs and is associated with a prolonged progression-free interval (multivariate HR 0.56, 95% CI 0.31–1.00, p = 0.050), with the effect direction preserved after immune and sex adjustment. Genome-wide differential expression and gene-set enrichment in an independent cohort (GSE193581) confirm that CREM-detected T cells are enriched for a TCR-driven immediate early transcriptional program, supporting the reinterpretation of CREM as a marker of TCR-driven IEG activation. Full article

Drug resistance arising during cancer development and progression remains a major challenge in the treatment of epidermal growth factor receptor (EGFR)-driven tumors, particularly those harboring the clinically relevant T790M/L858R double mutation. In this study, we developed an integrated computational workflow combining explainable machine learning, virtual screening, molecular dynamics simulations, and binding free-energy calculations to identify novel inhibitors of this drug-resistant EGFR variant. An XGBoost regression model was trained using scaffold-aware cross-validation, Bayesian hyperparameter optimization, and sequential feature selection, resulting in a compact model based on 16 molecular descriptors. The model demonstrated robust predictive performance on external validation data, while SHAP analysis identified descriptors related to the local electronic environment, fragment distribution, and molecular topology as the primary contributors to activity prediction. The optimized model was subsequently applied to screen compounds from the Enamine REAL database. Top-ranked candidates were evaluated using explicit-solvent molecular dynamics simulations and MM/GBSA binding free-energy calculations. Several compounds formed stable protein–ligand complexes and maintained key interactions with residues known to be important for EGFR inhibition, including Lys745, Met790, and Leu718. These results demonstrate that the proposed workflow can efficiently prioritize computational candidates of drug-resistant EGFR mutants and may support the development of new therapeutic strategies for overcoming resistance in EGFR-driven cancers. Full article

The discovery of activating epidermal growth factor receptor (EGFR) mutations transformed the management of non-small cell lung cancer and has driven two decades of therapeutic advances in precision oncology across metastatic, resectable, and unresectable locally advanced disease, including central nervous system (CNS) control. Consequently, treatment outcomes for patients with tumors harboring classical EGFR mutations have markedly improved. Despite these advances, many questions remain unanswered, and the expanding number of treatment options has created new challenges in treatment selection and sequencing. This narrative review summarizes contemporary data on the management of classical EGFR-mutant NSCLC, encompassing novel therapeutic approaches across disease stages, biomarker-informed resistance strategies, multimodality treatment integrating radiotherapy, CNS-directed management, and challenging scenarios such as small-cell transformation. We also discuss emerging fourth-generation inhibitors, nucleic-acid delivery platforms, and data-enabled personalized treatment. We highlight evolving standards of care, unresolved knowledge gaps, and research priorities for the next decade. Full article

Most cancers are fatal and remain challenging to cure due to changes in tumorigenesis and therapeutic resistance. Despite significant advancements in cancer therapy, a substantial proportion of malignancies exhibit resistance to conventional therapies, driven primarily by cancer plasticity and the emergence of multidrug resistance. Recent cancer treatments include cytotoxic chemotherapy, molecular targeted therapy, and immune checkpoint inhibitors. A major hallmark of cancer cells is their ability to develop sophisticated evasion mechanisms that bypass programmed cell death when exposed to anti-cancer drugs. In addition, malignant cells evade the efficacy of anti-cancer drugs by altering cell proliferation, survival, and metastasis. To suppress oncogenic characteristics, necroptosis-based therapies have attracted substantial attention, as they can inhibit tumorigenesis and improve treatment outcomes across many cancer types. Furthermore, an increasing body of research focuses on suppressing tumorigenesis by targeting receptors that are overexpressed in cancer cells. In this review, we elucidate how tumorigenesis is inhibited by regulating the epidermal growth factor receptor (EGFR)–tumor necrosis factor receptor (TNFR) signaling pathway in necroptosis. By delineating the underlying mechanisms of these receptors, we propose that the induction of necroptosis via EGFR and TNFR represents an innovative paradigm for targeted therapy, offering a strategy to enhance clinical outcomes in treatment-resistant cancers. Full article

Non-small cell lung cancer (NSCLC) comprises a diverse group of malignancies driven by distinct molecular alterations that have become critical targets for precision oncology. Among these, EGFR exon 20 insertion mutations and HER2 dysregulation, including HER2 mutations, amplification, and overexpression, define clinically important subsets of NSCLC characterized by unique biological behavior and historically limited treatment options. Although these alterations account for a relatively small proportion of NSCLC cases, their identification has become increasingly relevant due to advances in molecular diagnostics and the development of novel targeted therapies. This review provides a comprehensive overview of the epidemiology, molecular biology, and clinical characteristics of EGFR exon 20 insertion-mutated and HER2-deregulated NSCLC. We discuss current diagnostic approaches, including the role of next-generation sequencing and biomarker testing, and summarize the evolving therapeutic landscape encompassing conventional chemotherapy, immunotherapy, and targeted agents. Particular attention is given to recently approved therapies and emerging treatment strategies, including tyrosine kinase inhibitors and antibody-based therapies that have demonstrated clinically meaningful activity in these patient populations. We also address the major challenges associated with treatment resistance, molecular heterogeneity, and optimal therapeutic sequencing. Finally, we highlight ongoing research efforts and future perspectives aimed at improving outcomes for patients with these rare but clinically significant molecular subtypes of NSCLC. Full article

Background/Objectives: Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has undergone rapid therapeutic evolution. However, heterogeneous outcomes persist, driven by mutations, central nervous system (CNS) involvement, and dynamic tumor burden reflected in part by circulating tumor DNA (ctDNA). As such, this review aims to summarize the most recent risk stratification frameworks in treating EGFR-mutant NSCLC, evaluate evidence supporting treatment intensification strategies and managing adverse effects, and explore the evolving role of ctDNA in guiding personalized therapy. Methods: A comprehensive literature search was conducted using major medical databases with a focus on key relevant studies on the workup and management of EGFR-mutant NSCLC. All authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Molecular co-alterations, such as TP53 and RB1, as well as central nervous system (CNS) involvement, are consistently associated with inferior outcomes, supporting consideration of upfront treatment intensification. Combination strategies, including osimertinib plus chemotherapy or amivantamab-based regimens, demonstrate improved progression-free survival and delayed CNS progression when compared against osimertinib monotherapy. Intensification, however, is associated with a higher risk of increased toxicity, including dermatologic adverse events and infusion-related reactions. Finally, the utilization of circulating tumor DNA (ctDNA) has emerged as a strong prognostic marker, with ongoing trials investigating its predictive role for both escalation and de-escalation of therapy. Conclusions: The treatment paradigm for EGFR-mutant NSCLC is gradually evolving beyond first-line osimertinib to include a more integrated approach that considers molecular features, CNS involvement, and early ctDNA response. Although intensified regimens offer meaningful efficacy gains for high-risk patients, proactive toxicity management is essential to preserving quality of life. ctDNA-guided strategies represent a new and promising frontier for escalation and de-escalation of therapy, with results from ongoing trials poised to further refine personalized treatment algorithms. Full article

Nimotuzumab is a humanized anti-EGFR monoclonal antibody with a unique pharmacodynamic profile characterized by intermediate affinity and bivalent binding dependence, enabling density-selective tumor targeting while sparing normal tissues from the severe skin rash and other toxicities common to EGFR inhibitors. Since its first approval in 2002, nimotuzumab has been registered for eight cancer indications. Unlike conventional fixed-dose schedules, emerging evidence supports prolonged administration beyond initial combination therapy. This review summarizes clinical data from pancreatic cancer, esophageal cancer, high-grade glioma, pediatric diffuse intrinsic pontine glioma, head and neck squamous cell carcinoma, nasopharyngeal cancer and other solid tumors, showing that extended nimotuzumab exposure, often as maintenance monotherapy, may prolong overall survival, progression-free survival, and disease control compared to limited cycles. Despite heterogeneity in tumor types and treatment regimens, maintenance nimotuzumab was consistently associated with better results, particularly in terms of overall survival. Notably, significant survival benefits were observed in locally advanced SCCHN (24.9 vs. 12.5 months) and esophageal cancer (15.9 vs. 8.1 months) across independent clinical trials. Mechanistically, nimotuzumab exerts direct cytostatic effects via G1 arrest, potent anti-angiogenic activity through VEGF downregulation, indirect pro-apoptotic effects, and broad immunomodulation including ADCC, NK-DC cross-talk, EGFR-specific CD8+ T cell priming, upregulation of HLA class I, and favorable regulation of regulatory T cells. Its density-selective binding reduces selective pressure for acquired resistance. Future research priorities should include prospective randomized trials specifically evaluating maintenance strategies, biomarker-driven patient selection, the molecular characterization of resistance mechanisms, integration with immunotherapy and modern combination regimens, and the development of next-generation platforms, including antibody–drug conjugates and multi-specific constructs. Full article

Background/Objectives: The EGFR T790M mutation drives lung cancer resistance by sterically hindering inhibitors and restoring ATP affinity. As C797S mutations render covalent inhibitors obsolete, novel non-covalent strategies are critical. This study identifies inhibitors that redefine the mutant methionine sulfur as a primary stabilizing anchor rather than a liability. Methods: A generative AI framework (DrugEx) sampled 100,000 molecules, prioritized via QSAR classification (ROC-AUC: 0.91 ± 0.01) and Applicability Domain (AD) mapping. The workflow was de-risked through retrospective benchmarking against the DUD-E database (35,590 molecules), achieving a 1% Enrichment Factor of 5.19. Lead candidates underwent 100 ns all-atom molecular dynamics (MD) simulations. Mechanistic stability was quantified via Free Energy Landscape (FEL) analysis and ensemble-averaged MM-GBSA binding free energy calculations. Results: Candidate 106 demonstrated exceptional mutation tolerance by redistributing interactions toward the Met790 sulfur atom. MD analysis confirmed potency is dictated by successful recruitment of the thioether environment, locking the complex within a narrow thermodynamic basin. Candidate 106 maintained stable binding (−11.0 kcal/mol) corroborated by an equipotent MM-GBSA ΔG_bind of −50.51 kcal/mol in the mutant system, driven by persistent π-sulfur contacts (85% occupancy). Conclusions: These results indicates that potential T790M resistance bypass is achievable by exploiting the gatekeeper methionine’s electronic environment. This modeled mutation-aware framework provides a candidate non-covalent strategy to be validated in future wet-lab campaigns. Full article

Bispecific antibodies (bsAbs) have emerged as a novel therapeutic class in oncogene-driven non-small-cell lung cancer (NSCLC), designed to simultaneously target multiple signaling pathways and overcome resistance mechanisms associated with tyrosine kinase inhibitors (TKIs). Unlike small-molecule TKIs, bsAbs enable dual receptor blockade and immune effector engagement, offering a mechanistically distinct advantage in the context of tumor heterogeneity and bypass signaling. This review summarizes the structural and biological principles underlying bsAb design, with a focus on clinically approved agents such as amivantamab (EGFR/MET) and zenocutuzumab (HER2/HER3) and a growing pipeline of investigational agents. We evaluate key clinical evidence from Phase I-III trials including CHRYSALIS, PAPILLON, MARIPOSA, MARIPOSA-2 and eNRGy, and compare the efficacy, toxicity, and CNS penetration profile of bsAbs relative to TKIs and antibody–drug conjugates (ADCs). While bsAbs demonstrate meaningful clinical activity, particularly in TKI-resistant disease and molecularly defined subsets such as EGFR exon 20 insertions and NRG1 fusions, their limitations, including intravenous administration, increased immune-mediated and thromboembolic toxicity, currently preclude replacement of TKIs in most settings. Collectively, available evidence supports a complementary role for bsAbs within evolving multimodal treatment paradigms, particularly in combination strategies. Future directions include biomarker-driven patient selection, improved drug engineering and integration into adaptive therapeutic sequencing frameworks. Full article

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies widely used for the treatment of colorectal cancers. However, due to various mechanisms of resistance to these targeted therapies, the patients’ responses vary. These resistances remain a major obstacle in treatment and overcoming them has become a key emphasis of current therapeutic strategies. Intrinsic and acquired resistance often lead to reactivation of downstream signaling pathways, mainly the RAS-RAF-MEK-ERK (MAPK pathway) and PI3K-AKT axes. Prior existing mutations in KRAS, NRAS, and BRAF result in primary resistance by constantly activating the signals, irrespective of EGFR inhibition. That said, acquired resistance manifests under therapeutic burden through the process of clonal evolution via KRAS and BRAF alterations, restoring MAPK pathway activity despite EGFR inhibition. In addition to those mutations, tumor cells exploit mechanisms independent of EGFR, such as the pathway bypass, which includes amplification of ERBB family receptors like HER2 (ERBB2) and activation of MET signaling. To overcome these resistances, novel strategies have emerged, which target multiple nodes within the oncogenic networks. Such methods include vertical pathway inhibition, multi-kinase inhibition, liquid-biopsy-guided therapy, and anti-EGFR rechallenge. Reactivation driven by secondary mutation can be prevented by targeting multiple nodes within the MAPK cascade simultaneously, which is referred to as the vertical pathway inhibition. Overall, this review underscores that overcoming therapeutic resistance requires a multidimensional approach that integrates molecular profiling, rational combination therapies, and adaptive treatment. Finally, these advances underscore the shift toward precision oncology, where therapy is tailored to tumor evolution, leading to improved response and patient outcome. Full article

Cancer is a genetic disease driven by the accumulation of mutations that disrupt normal cellular growth. Among the most frequently mutated families are protein kinases, inositol polyphosphate kinases, and GTPases, which together function as central molecular switches controlling proliferation, survival, and metabolism. In cancer, activating mutations in protein kinases, such as EGFR and BRAF, lead to uncontrolled downstream signaling by locking these enzymes in a constitutively active state. Similarly, mutations affecting inositol kinases, notably PI3KCA, hyperactivate the PI3K/AKT pathway, promoting relentless cell survival and resistance to apoptosis. GTPases, particularly Ras family members (KRAS, NRAS, HRAS), are classical oncogenes where single amino acid substitutions impair their intrinsic GTP hydrolysis activity, trapping them in a persistently GTP-bound “on” state. This unleashes continuous mitogenic signaling independently of external growth factors. Collectively, these mutations are not random but converge on a limited set of core pathways, making them key drivers of tumor initiation and progression. Understanding the specific molecular consequences of kinase and GTPase mutations has directly informed the development of targeted therapies, including small molecule inhibitors and monoclonal antibodies, now used in routine clinical practice. Full article

Endocrine-disrupting chemicals (EDCs) are important environmental risk factors for urogenital malignancies, but the shared molecular mechanisms underlying their carcinogenic effects remain poorly understood. Here, we systematically investigated the common pro-tumorigenic mechanisms of 12 prevalent EDCs, including anthracene, benzo[a]pyrene (BaP), bisphenol A, clofenotane, di(2-ethylhexyl) phthalate, diazinon, dibutyl phthalate, glyphosate, malathion, perfluorooctanoic acid, polychlorinated biphenyls, and triclosan, across four urogenital cancers, including bladder cancer (BLCA), renal cell carcinoma (RCC), prostate adenocarcinoma (PRAD), and testicular germ cell tumor (TGCT). By integrating network toxicology and protein–protein interaction analysis, we identified shared hub targets linking EDC exposure to tumor progression. EGFR and CASP3 were identified as core targets in BLCA, EGFR and CASP9 in RCC, and CASP3, ESR1, and EGFR in PRAD, whereas KIT emerged as a broadly relevant target in TGCT. Molecular docking and molecular dynamics simulations supported the stable binding of EDCs to these targets. Among the predicted interactions, BaP showed strong binding affinity for CASP9 (ΔG = −9.8 kcal/mol) and was therefore selected for experimental validation. Analysis of TCGA data showed that elevated CASP9 expression was significantly associated with poorer overall survival in patients with RCC. In 786-O and ACHN cells, chronic exposure to an environmentally relevant concentration of BaP significantly increased CASP9 protein stability without altering its mRNA expression, suggesting post-transcriptional regulation. Collectively, these findings identify shared molecular targets of EDCs across urogenital cancers and provide new mechanistic insight into EDC-driven tumor progression, prioritizing potential biomarkers and therapeutic targets for environmentally related malignancies. Full article

Background/Objectives: Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, driven by invasive behavior and frequent resistance to systemic therapies. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) benefit patients with EGFR-mutant NSCLC, but their efficacy is often limited by tumor-intrinsic and environmental resistance mechanisms. Benzo[a]pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon from tobacco smoke, combustion, and dietary sources, is a known carcinogen; however, its role in modulating therapeutic responses is poorly understood. Studies, including ours, implicate the platelet-activating factor-receptor (PAFR) pathway in mediating environmental pollutant and therapy-induced effects on tumor growth and microvesicle particle (MVP) release. We hypothesized that PAFR activation mediates BaP-induced NSCLC progression and influences EGFR-TKI responses. Methods: We assessed the effects of BaP, PAFR agonist CPAF, EGFR-TKIs, and their combinations on cell viability, proliferation, migration, anchorage-independent growth, and MVP secretion. Results: BaP did not alter cell survival but significantly increased migration, growth, colony formation, and MVP release, similar to CPAF, and these effects were blocked by a PAFR antagonist or acid sphingomyelinase inhibitor. Notably, BaP did not significantly reduce EGFR-TKI efficacy at tested concentrations. Conclusions: These results show that environmental carcinogens modulate NSCLC behavior through PAFR signaling without compromising EGFR-TKI responsiveness, highlighting PAFR as a potential therapeutic target. Full article

Background: Non-small-cell lung cancer (NSCLC) research has transitioned from tumor-intrinsic mechanisms to immune-driven therapeutic innovation; however, the translation of mechanistic insights into clinically actionable strategies remains incompletely defined. Methods: A total of 1213 records were retrieved from the Web of Science Core Collection (SCI-Expanded) (2009–2025). After data cleaning and duplicate removal (n = 13), 1200 publications were analyzed. Bibliometrix (R) and CiteSpace were used for performance analysis, keyword mapping, thematic evolution, and co-citation clustering. Results: Annual scientific production increased markedly after 2018, paralleling the expansion of immunotherapy. Keyword co-occurrence identified three major thematic domains (>40 high-frequency keywords) linking molecular mechanisms, biomarkers, and therapeutic strategies. Thematic mapping highlighted immunotherapy, tumor microenvironment, and PD-1 as dominant motor themes, while resistance-related pathways formed a central mechanistic–translational axis. Thematic evolution demonstrated a shift from EGFR-targeted therapy to epithelial–mesenchymal transition (EMT)-centered resistance and subsequently to immune-dominant strategies. Co-citation clustering produced robust structures (Q ≈ 0.62; silhouette ≈ 0.84), identifying EMT as a persistent mechanistic hub. Pilot ELISA validation confirmed significant increases in TGF-β1 (~2.05-fold), IL-6 (~2.59-fold), CCL2 (~2.10-fold), and PD-L1 (~2.56-fold) under EMT-inducing conditions (p < 0.01). Conclusions: This integrative approach provides a quantitative and experimentally supported framework linking mechanistic insights to therapeutic innovation in NSCLC. Full article

Approximately 30% of all human cancers are driven by mutations in RAS genes, KRAS, HRAS, and NRAS, resulting in the constitutive activation of RAS proteins and stimulation of MAPK/AKT signaling. Non-mutant, i.e., wild-type (WT) RAS can also become activated through mechanisms such as gene amplification or excessive stimulation by mutated or overexpressed receptor tyrosine kinases (e.g., EGFR), thereby promoting cancer progression. Mutant or activated RAS contributes to multiple hallmarks of cancer, including unchecked cellular proliferation, reprogrammed cellular metabolism, immunosuppression, and metastasis. Hence, RAS is of immense clinical importance, with hundreds of laboratories studying various aspects of RAS biology or developing RAS inhibitors. There is perhaps no greater unmet medical need in oncology than the need for a broadly efficacious but safe inhibitor of mutant and activated RAS. Mutant-specific KRAS G12C inhibitors have shown promising therapeutic efficacy, leading to FDA approval of sotorasib and adagrasib, although their use is limited to patients with the relatively rare G12C KRAS mutation. Mutant-specific KRAS inhibitors are also susceptible to adaptive resistance, in part, due to secondary RAS mutations, and compensatory signaling from WT RAS isozymes. A pan-RAS inhibitor capable of blocking all RAS isozymes, regardless of the underlying mutation, offers the potential for broader efficacy and capacity to avert resistance. While just a few years ago, pan-RAS inhibitors were predicted to be severely toxic or even fatal, the apparent safety profile of RMC-6236 (daraxonrasib), a pan-RAS inhibitor currently in clinical trials, suggests otherwise. Indeed, pan-RAS inhibitors are now considered by many in the RAS field to be the most promising class in development. In this review, we summarize the evolution and current status of pan-RAS and pan-KRAS inhibitors in preclinical and clinical development and highlight emerging human-relevant tumor models that are advancing preclinical evaluation. Full article