第三代EGFR-TKI耐药性机制及联合用药治疗的策略  

Drug Resistance Mechanism of Third Generation EGFR-TKI and TherapeuticStrategy of Drug Combination

作　　者：周建宇 秦晓红 米立志 ZHOU Jian-Yu;QIN Xiao-Hong;MI Li-Zhi(School of Life Sciences,Tianjin University,Institute of Structural and Molecular Biology,Tianjin 300072,China)

机构地区：[1]天津大学生命科学学院结构与分子生物学系,天津300072

出　　处：《中国生物化学与分子生物学报》2024年第2期170-179,共10页Chinese Journal of Biochemistry and Molecular Biology

摘　　要：表皮生长因子受体(epidermal growth factor receptor,EGFR)是一种受体酪氨酸激酶,参与如细胞的增殖、分裂和分化等生理过程,并在肿瘤的发生和发展中发挥重要作用。在非小细胞肺癌的靶向治疗中,靶向表皮生长因子受体的酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)取得了显著疗效。然而,伴随着EGFR T790M等突变的出现,患者会对第一代和第二代EGFR-TKI治疗产生耐药性。为此,开发的以奥希替尼(Osimertinib)为代表的第三代EGFR-TKI,在治疗携带EGFR T790M突变患者的耐药中取得了良好效果。但部分接受第三代EGFR-TKI治疗的患者仍会产生获得性耐药。目前,已知的耐药机制主要分为EGFR依赖型(EGFR自身激酶结构域突变)和EGFR非依赖型(异常旁路信号的激活、下游信号通路的激活、组织学表型转变)两类。本文对EGFR及第三代EGFR-TKI药物结构、主要的耐药机制和耐药后的治疗策略进行了全面综述与总结,并对未来克服EGFR-TKI耐药性的可能方向进行了分析。Epidermal growth factor receptor(EGFR)is a receptor tyrosine kinase that participates in physiological processes such as cell proliferation,division,and differentiation.EGFR plays an important role in the occurrence and development of tumors.In targeted treatment of non-small cell lung cancer,tyrosine kinase inhibitors(TKIs)targeting EGFR have achieved significant efficacy.However,with the emergence of mutations such as EGFR T790M,patients may develop resistance to the first and second-generation EGFR TKI therapy.Therefore,the third generation EGFR TKI,represented by Osimertinib,has achieved good results in patients with EGFR T790M mutations.However,some patients still develop acquired drug resistance after third generation EGFR TKI treatment.Currently,the drug resistance mechanisms are mainly divided into two types:EGFR dependent(mutations in the EGFR kinase domain)and EGFR independent(activation of abnormal bypass signals and downstream signal pathways,and histological phenotypic changes).This article comprehensively reviews and summarizes the structure and main drug resistance mechanisms of the third generation TKI,and the treatment strategies after drug resistance and the possible directions for overcoming EGFR TKI resistance in the future are also analyzed.

关 键 词：表皮生长因子受体 酪氨酸激酶抑制剂 奥希替尼 耐药机制 联合用药 

分 类 号：Q71[生物学—分子生物学]