KRAS-Targeted Therapy in Non–Small Cell Lung Cancer: Current Standards, Resistance Mechanisms, and Emerging Therapeutic Strategies

KRAS G12C-Targeted Therapy Strategy for Lung Cancer: Mechanism, Clinical Practice and Challenges

This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.

KRAS G12C-mutated Metastatic Colorectal Cancer: Current Therapeutic Strategies and Future Directions

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.

Recent advances in EGFR-targeted therapies for non-small cell lung cancer

ABSTRACT Introduction The discovery of epidermal growth factor receptor (EGFR) mutations has deeply reshaped the treatment of non-small cell lung cancer (NSCLC). Throughout the last years, third-generation tyrosine kinase inhibitor (TKI) osimertinib in monotherapy has been the standard of care; however, resistance limits durable responses, necessitating novel combinations and sequencing strategies. Areas covered This review discusses recent advances in EGFR-targeted therapies within the molecular landscape of classical and uncommon EGFR mutations, focusing on frontline intensification strategies in metastatic disease—specifically TKI combinations with chemotherapy (FLAURA2) or bispecific antibodies (MARIPOSA)—and emerging post-progression strategies to overcome acquired resistance mechanisms. A comprehensive literature search (January 2021–March 2026) was conducted via PubMed, and recent major oncology conference proceedings (ASCO, ESMO, WCLC, ELCC) and clinical trial registries for ongoing studies. Expert opinion The therapeutic landscape is shifting from a uniform frontline TKI monotherapy approach toward biomarker-driven, risk-stratified, intensification. High-risk patients (e.g. TP53 co-mutations, L858R) derive significant benefit from combination regimens, whereas mono-TKI remains appropriate for favorable prognostic subgroups. Future progress relies on validating predictive biomarkers—particularly circulating tumor DNA (ctDNA) dynamics—to guide adaptive treatment strategies, balancing efficacy gains against toxicity and costs, while ensuring equitable global access to novel therapies.

From KRAS inhibition to tumor adaptation: mechanistic layers of resistance and therapeutic strategies.

This review synthesizes current knowledge on KRAS resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies.

Targeting KRAS in Cancer: Advances in Precision Oncology and Drug Development

These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy, however, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.