TL;DR
This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.
Cancer frequently arises from the impaired functioning of the Mitogen-activated protein kinase (MAPK) signaling system, driven by mutation or overexpression of key signaling components. RAF, MEK, ERK, and KRAS inhibitors have significantly improved clinical outcomes, but efficacy is still restricted due to pathway reactivation, adaptive resistance, and signaling cross-talk. These limitations have led to the search for novel therapeutic approaches and molecular targets in the MAPK network. Melanoma, thyroid carcinoma, and pancreatic adenocarcinoma were selected because MAPK pathway alterations contribute to their pathogenesis and influence treatment response. This review examines the biological importance of MAPK signaling in these cancers and discusses MAPK-targeted therapies, mechanisms of resistance, and combination treatment options. It also addresses the expanding evidence on natural compounds that modulate MAPK- related signaling networks and reviews recent transcriptomic findings that have enhanced the identification of clinically relevant molecular targets. Additionally, MAP4K4 has been linked to tumor progression and metastasis, and poor clinical outcomes, indicating its potential as a therapeutic target for future clinical studies. The findings presented in this review suggest that combining transcriptomic evidence with molecular and pharmacological analyses could aid target prioritization and accelerate the development of targeted strategies for MAPK-driven malignancies.
Non-Small Cell Lung Cancer (NSCLC) remains a major clinical challenge and is one of the leading causes of cancer-related mortality worldwide. Its poor prognosis is driven by substantial molecular heterogeneity, dynamic interactions between tumor cells and the surrounding microenvironment, and the frequent development of therapeutic resistance. Among the signaling pathways involved, Focal Adhesion Kinase (FAK) and Proline-rich tyrosine Kinase 2 (PYK2) have emerged as important regulators that integrate oncogenic and microenvironmental signals, thereby promoting tumor progression and resistance to therapy. A narrative literature review was conducted using major scientific databases to evaluate the mechanistic, preclinical, and clinical evidence regarding the role of FAK/PYK2 signaling in NSCLC. Studies investigating pathway interactions, mechanisms of therapeutic resistance, combination treatment strategies, and nanocarrier-mediated drug delivery systems were critically analyzed. FAK and PYK2 function as central signaling hubs that connect key oncogenic pathways, including Epidermal Growth Factor Receptor (EGFR), Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), Mitogen-Activated Protein Kinase (MAPK), and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. Activation of these kinases promotes cell proliferation, survival, epithelial–mesenchymal transition, and therapeutic resistance. Although FAK/PYK2-targeted monotherapy has demonstrated limited clinical efficacy, rational combination strategies involving EGFR tyrosine kinase inhibitors, MAPK inhibitors, chemotherapy, or immunotherapy have shown promising synergistic effects. In addition, nanocarrier-based delivery systems may improve drug targeting and pharmacokinetic profiles while reducing systemic toxicity. The adaptive quality of the disease calls for multi-pathway therapeutic strategies for the treatment of NSCLC. Blocking FAK/PYK2 may interrupt the integrated signaling pathways and compensatory mechanisms that contribute to resistance. Precision-guided combination regimens aided by the use of biomarker-driven patient selection are critical when it comes to improving clinical outcomes. FAK and PYK2 represent promising therapeutic targets in NSCLC. Strategies involving multi-pathway inhibition and advanced drug delivery platforms offer a rational approach to suppress tumor growth and overcome therapeutic resistance. Further investigation in translational and clinical settings is warranted to establish their therapeutic potential.
Lung cancer, a leading cause of cancer-related mortality, is often driven by mutations in the key oncogenes epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma virus (KRAS). Despite advancements of targeted therapies such as tyrosine kinase inhibitors, resistance remains a significant hurdle. Overexpression of HER3, associated with poor prognosis in non-small cell lung cancer (NSCLC), presents an alternative therapeutic target. In this study, we investigate the efficacy of the HER3-targeting antibody-drug conjugate HER3-DXd and its synergistic potential when combined with cell cycle and DNA damage response modulators. A significant synergy is observed with PARP inhibitors, effective in both EGFR- and KRAS-mutated NSCLC models. This combination markedly enhances DNA damage, induces apoptosis, and slows down in vivo tumor progression. Notably, this regimen also triggers antibody-dependent immunomodulatory effects through cGAS-STING pathway activation, potentiating innate immune cells for tumor killing. Our findings suggest that combining HER3-DXd with PARP inhibitors offers a promising therapeutic approach, effectively targeting diverse NSCLC subtypes.
Regulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell's perception of its environment is not clear. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncoprotein that suppresses transmembrane EGFR signaling in cancer cells. ALK inhibition restores signaling through EGFR, thereby promoting survival and drug tolerance. Here, we tested whether such modulation of EGFR activity was common among other RTK fusions, which collectively are found in ~5% of all cancers. Using live- and fixed-cell microscopy in isogenic and patient-derived cell lines, we found that a wide variety of RTK fusions suppress transmembrane EGFR, through mechanisms that include the sequestration of the adaptor protein Grb2. Targeted therapies rapidly released Grb2 from sequestration and potentiated EGFR. Synthetic optogenetic analogs of RTK fusions confirmed that cytoplasmic sequestration of Grb2 was sufficient to suppress perception of extracellular EGF and could do so without driving signaling from the synthetic fusion itself, demonstrating that fusion signaling and suppression of EGFR signaling could be functionally decoupled. Our study uncovers that a large number of RTK fusions simultaneously act as both activators and suppressors of signaling, the mechanisms of which could be exploited for biomimetic therapies that enhance cell killing and suppress drug tolerance.
The molecular mechanisms by which the UPS contributes to targeted therapy resistance in NSCLC are summarized, recent progress in emerging UPS-targeting strategies are evaluated, and the major barriers impeding their clinical translation are critically discussed.
The persistent emergence of resistance underscores that current targeted therapies, while revolutionary, are primarily disease-modifying rather than curative, necessitating continuous innovation to overcome the inherent biological challenge of tumor adaptability and heterogeneity.
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