Mutations in EGFR (mEGFRs) in non-small cell lung cancer (NSCLC) are key factors driving tumor development and treatment response. The present article aimed to review the classification, characteristics and molecular mechanisms of resistance to third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) associated with mEGFRs. Activating mutations (such as L858R and exon 19 deletions) are the primary markers of sensitivity to EGFR-TKIs, while rare mutations (such as G719X and S768I) require individualized treatment strategies. Resistance mechanisms are categorized into EGFR-dependent (such as T790M and C797S mutations) and -independent (bypassing signaling activation, epithelial-mesenchymal transition, tumor microenvironment remodeling and epigenetic regulation). Third-generation EGFR-TKIs (such as osimertinib) markedly improve patient survival by selectively targeting the T790M mutation, but novel resistance mutations, such as C797S, limit their long-term efficacy. Combination therapies (such as MET proto-oncogene, receptor tyrosine kinase/EGFR dual-target inhibitors) and fourth-generation TKIs (such as BLU-945) offer novel directions to overcome resistance. Future research should focus on precise subtyping, dynamic monitoring of resistance mechanisms and regulation of the immune microenvironment to advance personalized treatment for NSCLC.

Keywords: EGFR mutation; drug resistance; non-small cell lung cancer; targeted therapy; third-generation EGFR-tyrosine kinase inhibitor.

Copyright: © 2025 Tian et al.

非小细胞肺癌（NSCLC）中表皮生长因子受体（EGFR）突变（mEGFRs）是驱动肿瘤发展和治疗反应的关键因素。本文旨在回顾与 mEGFR 相关的第三代 EGFR 酪氨酸激酶抑制剂 (EGFR-TKIs) 耐药性相关的分类、特征及分子机制。激活突变（如 L858R 和第 19 外显子缺失）是 EGFR-TKIs 敏感性的主要标志，而罕见突变（如 G719X 和 S768I）需要个体化的治疗策略。耐药机制可分为依赖 EGFR 的（如 T790M 和 C797S 突变）和不依赖 EGFR 的（旁路信号激活、上皮-间充质转化、肿瘤微环境重塑及表观遗传调控）。第三代 EGFR-TKIs（如奥希替尼）通过选择性靶向 T790M 突变显著改善患者生存期，但新出现的耐药突变（如 C797S）限制了其长期疗效。联合疗法（如 MET 原癌基因、受体酪氨酸激酶/EGFR 双重抑制剂）和第四代 TKIs（如 BLU-945）提供了克服耐药性的新方向。未来的研究应重点关注精确分型、耐药机制的动态监测及免疫微环境调控，以推进 NSCLC 的个性化治疗。

关键词：
EGFR 突变；药物耐药性；非小细胞肺癌；靶向治疗；第三代 EGFR 酪氨酸激酶抑制剂。

版权：© 2025 Tian et al.