非小细胞肺癌EGFR-TKIs靶向治疗耐受机制的研究进展

Research progress on resistance mechanism of EGFR-TKIs targeted therapy for non-small cell lung cancer

非小细胞肺癌(NSCLC)是肺癌中占比最高的组织学亚型。自从发现NSCLC驱动基因突变以后,NSCLC的药物治疗从常规化疗发展到分子靶向治疗。表皮生长因子受体(EGFR)是NSCLC最重要的驱动基因之一,靶向突变型EGFR的酪氨酸激酶抑制剂(TKIs)已开发出一、二、三代药物并应用于临床,EGFR-TKIs靶向治疗可显著提高NSCLC患者的无进展生存期(PFS)和总生存期(OS)。然而,大部分NSCLC患者在接受EGFR-TKIs靶向治疗后的10~18个月均不可避免地出现耐药现象。针对EGFR-TKIs耐药机制研究近年来已取得的重大进展,本文拟从EGFR再突变、信号旁路激活、细胞谱系转换及肿瘤微环境等方面对其进行简要评述。

Non-small cell lung cancer(NSCLC)is the histological subtype with highest proportion of lung cancer.Since the discovery of NSCLC driver gene mutations,the drug treatment of NSCLC had evolved from conventional chemotherapy to molecular targeted therapy.Epidermal growth factor receptor(EGFR)was one of the most important driver genes of NSCLC.Three generations of tyrosine kinase inhibitors(TKIs)targeting mutant EGFR had been developed and applied to the clinic,and EGFR-tKIs Targeted therapy had significantly improved the progression-free survival(PFS)and overall survival(OS)of patients with NSCLC.However,most NSCLC patients inevitably developed drug resistance within 10-18 months after receiving targeted therapy with EGFR-TKIs.Great progress had been made on the research of EGFR-TKIs resistance mechanism in recent years.This article intended to briefly review the resistance mechanism of EGFR-TKIs targeted therapy in terms of EGFR secondary mutation,signal bypass activation,cell lineage switching and tumor microenvironment,etc.