Zhong Wen-Zhao, Zhou Qing, Wu Yi-Long
Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China.
Oncotarget. 2017 Aug 17;8(41):71358-71370. doi: 10.18632/oncotarget.20311. eCollection 2017 Sep 19.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been established as the standard therapy for -sensitizing mutant advanced non-small-cell lung cancer (NSCLC). However, patients ultimately develop resistance to these drugs. There are several mechanisms of both primary and secondary resistance to EGFR-TKIs. The primary resistance mechanisms include point mutations in exon 18, deletions or insertions in exon 19, insertions, duplications and point mutations in exon 20 and point mutation in exon 21 of gene. Secondary resistance to EGFR-TKIs is due to emergence of T790M mutation, activation of alternative signaling pathways, bypassing downstream signaling pathways and histological transformation. Strategies to overcome these intrinsic and acquired resistance mechanisms are complex. With the development of the precision medicine for advanced NSCLC, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account resistance mechanism. Though combination therapy is emerging as the standard of to overcome resistance mechanisms. Personalized treatment modalities based on molecular diagnosis and monitoring is essential for disease management. Emerging data from the ongoing clinical trials on combination therapy of third generation TKIs and antibodies in mutant NSCLC are promising for better survival outcomes.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）已被确立为致敏突变型晚期非小细胞肺癌（NSCLC）的标准治疗方法。然而，患者最终会对这些药物产生耐药性。对EGFR-TKIs产生原发性和继发性耐药的机制有多种。原发性耐药机制包括18外显子点突变、19外显子缺失或插入、20外显子插入、重复和点突变以及 基因21外显子点突变。对EGFR-TKIs的继发性耐药是由于T790M突变的出现、替代信号通路的激活、下游信号通路的绕过和组织学转化。克服这些内在和获得性耐药机制的策略很复杂。随着晚期NSCLC精准医学的发展，可用的全身和局部治疗选择有所增加，这需要考虑耐药机制的新临床算法。尽管联合治疗正成为克服耐药机制的标准方法。基于分子诊断和监测的个性化治疗模式对疾病管理至关重要。正在进行的关于第三代TKIs与抗体联合治疗 突变型NSCLC的临床试验的新数据有望带来更好的生存结果。
