Zhou Xuexue, Zeng Liang, Huang Zhe, Ruan Zhaohui, Yan Huan, Zou Chun, Xu Shidong, Zhang Yongchang
Medical College, Jishou University, Jishou, China.
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Cancer Med. 2025 May;14(9):e70921. doi: 10.1002/cam4.70921.
The seminal identification of epidermal growth factor receptor (EGFR) mutations as pivotal oncogenic drivers in non-small cell lung cancer (NSCLC) has catalyzed the evolution of biomarker-guided therapeutic paradigms for advanced disease. Currently, third-generation EGFR tyrosine kinase inhibitors (EGFR-TKI) have revolutionized first-line treatment for advanced EGFR-mutated NSCLC, yet acquired resistance remains an inevitable and formidable clinical challenge. This review systematically summarizes molecular mechanisms underlying treatment resistance, with a focus on clinical challenges associated with central nervous system (CNS) metastases. Therapeutic resistance mechanisms are categorized into EGFR-dependent (on-target) pathways, typified by acquired kinase domain mutations (e.g., C797S), and EGFR-independent (off-target) pathways, involving compensatory activation of parallel signaling effectors (e.g., MET amplification, HER2 activation) or phenotypic transformation. We further evaluated contemporary diagnostic modalities for identifying resistance drivers and appraised emerging therapeutic strategies, including fourth-generation EGFR-TKI, various combination therapies, and antibody-drug conjugates (ADCs), and so forth, with emphasis on ongoing clinical trials that may transform the existing treatment paradigm. By synthesizing preclinical and clinical insights, this review aims to advance mechanistic understanding and propose therapeutic strategies to overcome acquired resistance to third-generation EGFR-TKI in first-line treatment.
表皮生长因子受体（EGFR）突变作为非小细胞肺癌（NSCLC）关键致癌驱动因素的开创性发现，推动了晚期疾病生物标志物指导治疗模式的发展。目前，第三代EGFR酪氨酸激酶抑制剂（EGFR-TKI）彻底改变了晚期EGFR突变NSCLC的一线治疗，但获得性耐药仍然是一个不可避免且严峻的临床挑战。本综述系统总结了治疗耐药的分子机制，重点关注与中枢神经系统（CNS）转移相关的临床挑战。治疗耐药机制分为EGFR依赖（靶向）途径，以获得性激酶结构域突变（如C797S）为代表，以及EGFR非依赖（非靶向）途径，涉及平行信号效应器的代偿性激活（如MET扩增、HER2激活）或表型转化。我们进一步评估了用于识别耐药驱动因素的当代诊断方法，并评估了新兴的治疗策略，包括第四代EGFR-TKI、各种联合疗法和抗体药物偶联物（ADC）等，重点关注可能改变现有治疗模式的正在进行的临床试验。通过综合临床前和临床见解，本综述旨在深化机制理解，并提出治疗策略以克服一线治疗中对第三代EGFR-TKI的获得性耐药。
