Research progress of EGFR-TKI resistance mechanism and treatment strategy in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) activating mutations are pivotal driver alterations in non-small cell lung cancer (NSCLC), with a markedly higher prevalence in Asian populations, female patients, and never-smokers relative to other subgroups. EGFR tyrosine kinase inhibitors (TKIs) have been established as the first-line standard-of-care therapy for EGFR-mutant NSCLC. The third-generation agent osimertinib significantly improves survival outcomes, with a confirmed median progression-free survival (PFS) of 18.9 months in the first-line setting based on the FLAURA pivotal trial. Nevertheless, acquired resistance universally develops within a finite treatment period, and primary resistance occurs in a subset of patients, collectively constituting the major clinical bottleneck limiting durable therapeutic benefits. EGFR-TKI resistance is characterized by substantial complexity and inter- and intra-tumoral heterogeneity, driven by a spectrum of genetic and non-genetic adaptive mechanisms. Notably, distinct resistance mechanisms differ substantially in clinical actionability, defined as the feasibility of clinical detection, availability of targeted therapeutic options, and potential for clinical translation. Existing review studies mainly categorize EGFR-TKI resistance based on genetic mutation types but fail to integrate clinical practicality, resulting in ambiguous hierarchical logic and limited clinical guiding value. To address this gap, the present review systematically reorganizes and classifies EGFR-TKI resistance mechanisms strictly based on clinical actionability and intervention feasibility, constructing a standardized three-tier hierarchical framework: clinically actionable core resistance mechanisms with mature clinical intervention regimens, potentially actionable auxiliary mechanisms with preclinical evidence but limited clinical validation, and refractory primary resistance mechanisms without routine effective intervention strategies. Specifically, core actionable mechanisms include EGFR on-target secondary mutations and compensatory bypass pathway activation, which are well-validated in clinical cohorts and correspond to mature targeted therapies; potentially actionable mechanisms cover tumor phenotypic transformation, metabolic reprogramming, epigenetic modification, autophagy dysregulation, and tumor microenvironment abnormalities, all of which are supported by robust preclinical data but lack large-scale prospective clinical verification; refractory primary resistance is attributed to inherent tumor genetic backgrounds and host individual factors that currently cannot be effectively targeted in routine clinical practice. On the basis of this hierarchical classification, we further correlate each tier of resistance mechanisms with corresponding targeted therapeutic strategies, including next-generation EGFR-TKIs, pathway-specific combination targeted therapy, novel translational therapeutics, metabolic intervention, and traditional Chinese medicine (TCM)-derived natural product adjuvant therapy. This study aims to clarify the hierarchical logical relationship of heterogeneous EGFR-TKI resistance mechanisms, provide evidence-based references for individualized post-resistance clinical decision-making, and offer feasible directions for subsequent translational research and therapeutic optimization.