Dong Lijun, Lei Dan, Zhang Haijun
Department of Oncology, Zhongda Hospital, Southeast University, Nanjing, China.
Oncotarget. 2017 Aug 4;8(38):64600-64606. doi: 10.18632/oncotarget.19925. eCollection 2017 Sep 8.
Epidermal growth factor receptor () mutations () occur in 10-35% of non-small-cell lung cancer (NSCLC) cases and confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). TKIs are standard treatments for NSCLC patients harboring exon 19 deletions or exon 21 L858R point mutations. Despite initial benefit, most patients develop drug resistance, posing a challenge to oncologists. The secondary T790M point mutation in exon 20 contributes to approximately 60% of resistance cases. Optimum strategies for overcoming acquired EGFR TKI resistance are not clearly defined, although current common practice is to switch to platinum-based chemotherapy following resistance onset. While the second-generation EGFR TKIs, including afatinib, dacomitinib, and neratinib, exhibit promising preclinical activity against T790M mutants, dose-limiting toxicities in patients have limited clinical success. However, third generation EGFR TKIs appear able to overcome this mutation. Other treatment options aimed at EGFR TKI resistance include use of an EGFR TKI beyond progression, and chemotherapy plus an EGFR TKI. This review focuses on improved anticancer agents and therapy options for NSCLC patients with acquired EGFR TKI resistance.
表皮生长因子受体（EGFR）突变发生在10%-35%的非小细胞肺癌（NSCLC）病例中，并使患者对EGFR酪氨酸激酶抑制剂（TKIs）敏感。TKIs是携带EGFR外显子19缺失或外显子21 L858R点突变的NSCLC患者的标准治疗方法。尽管初始治疗有效，但大多数患者会产生耐药性，这给肿瘤学家带来了挑战。EGFR外显子20中的继发性T790M点突变约占耐药病例的60%。目前克服获得性EGFR TKI耐药的最佳策略尚不明确，尽管目前的常见做法是在耐药发生后改用铂类化疗。虽然第二代EGFR TKIs，包括阿法替尼、达可替尼和来那替尼，对T790M突变体显示出有前景的临床前活性，但患者的剂量限制性毒性限制了临床疗效。然而，第三代EGFR TKIs似乎能够克服这种突变。其他针对EGFR TKI耐药的治疗选择包括在疾病进展后继续使用EGFR TKI，以及化疗加EGFR TKI。本综述重点关注针对获得性EGFR TKI耐药的NSCLC患者的改良抗癌药物和治疗选择。
