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.
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.
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.
It is suggested that combining HER3-DXd with PARP inhibitors with a significant synergy is observed with PARP inhibitors, effective in both EGFR- and KRAS-mutated NSCLC models, effectively targeting diverse NSCLC subtypes.
It is uncovered 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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