TKI耐药后针对T790M突变治疗

TKI Resistance for T790M Mutation

表皮生长因子受体(epidermal growth factor receptor,EGFR)的口服活性小分子抑制剂的开发为非小细胞肺癌(non-small cell lung cancer,NSCLC)提供了新的治疗方案。EGFR基因发生激活突变的患者对EGFR酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)治疗敏感,该疗法使大量患者临床获益。第一代可逆型ATP-竞争型EGFR-TKIs,吉非替尼和厄洛替尼作为一线、二线或维持疗法具有疗效。尽管这些药物具有初始疗效,但大多数患者在1年内会产生抗药性,50%-60%的患者都与T790M管家基因出现突变有关。新近的不可逆型EGFR-TKIs-阿法替尼和dacomitinib可共价结合并抑制多个Erb B家族的受体(EGFR、HER2和HER4)。人们主要评价这些药物作为一线治疗的意义,以及在对第一代EGFR-TKIs产生获得性抗药性情况下的意义。阿法替尼是获批的第一种Erb B家族阻断剂,用于治疗带有EGFR激活突变的NSCLC患者;dacomitinib正处在临床开发的后期阶段。特异性靶向T790M抗药性突变的EGFR抑制剂(AZD9291、CO-1686、HM61713)正处在早期开发阶段。正如本文中的讨论,EGFR-TKIs靶向的激酶范围不同,它们结合EGFR受体的可逆性和药物相互作用的潜能也不同。对于临床医生来说,这些差异对经多种药物治疗的NSCLC患者具有意义,从创新型抗癌药物联合治疗策略的角度看,这些差异也极具意义。

Background and objective Epidermal growth factor receptor （EGFR） the development of orally activesmall molecule inhibitors for non-small ceU lung cancer （NSCLC） provides anew treatment plan. EGFR gene mutation in patients with activation EGFR tyrosine kinase inhibitor （EGFR-TKIs） therapy for the treatment of sensitive, so that a large number of clinical benefit. The first generation of reversible ATP-competitive EGFR-TKIs, gefitinib and erlotinib as first-line, second-line or has the effect of maintenance therapy. Although the initial effect of these drugs have, but most patients will produce drug resistance. Within a year, 50%-60% patients had T790M housekeeping gene mutation associated with. Irreversible EGFR-TKIs recent background： afatinib and dac-omitinib covalent binding and inhibition of multiple ErbB family receptors （EGFR, HER2 and HER4）. People evaluate these drugs as first-line treatment of significance, and acquired drug resistance situation significance on the first generation EGFR-TKIs. Afatinib is the first ErbB family approved blocking agent, used to treat with EGFR activatingmutations in patients with non small cell lung cancer; dacomitinib are in the later stages of clinicaldevelopment. EGFR inhibitors specifically targeting T790M resistance mutations （AZD9291, CO-1686, HM61713） are in the early stages of development. As discussed in this paper, the scope of the EGFK-TKIs kinase to target different, EGFK receptor binding was reversible and drug interaction potential is also different. For clinicians, these differences of the multi drug treatment of patients with non-small cell lung cancer with meaning, from the innovative anticancer drug combination therapy strategy point of view, these differences are also of great significance.