Phase I - Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA) Antwerp University Hospital, Edegem, Belgium.
Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Cancer Treat Rev. 2014 Sep;40(8):990-1004. doi: 10.1016/j.ctrv.2014.05.009. Epub 2014 Jun 6.
Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs.
This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation.
Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗可使携带有激活 EGFR 突变的非小细胞肺癌（NSCLC）患者产生肿瘤反应。然而，即使在持久的反应中，对 EGFR TKI 的耐药性也不可避免地会发生。
这篇综述检查了 EGFR TKI 治疗的耐药机制，这些机制主要源于继发的 EGFR 突变。其他诱导耐药的过程包括间质上皮转化因子（MET）扩增、上皮间质转化、从 NSCLC 向小细胞肺癌的表型变化，以及平行信号通路的改变。目前克服这些 EGFR TKI 耐药机制的治疗策略集中在抑制或阻断 ErbB 家族的多个成员。几种针对多个 ErbB 受体的分子正在 NSCLC 和其他适应症中进行研究，包括 afatinib（一种 ErbB 家族阻滞剂）以及 dacomitinib 和 lapatinib。目前正在临床开发中，针对非喹唑啉类 EGFR 激活和耐药（T790M）突变的新型 EGFR 抑制剂。其他治疗策略包括抑制平行和下游途径，使用靶向热休克蛋白（HSP）90 或聚（ADP-核糖）聚合酶的药物，以及哺乳动物雷帕霉素靶蛋白（mTOR）、针对胰岛素样生长因子-1 受体的单克隆抗体和 fulvestrant 介导的雌激素受体调节。
对 EGFR TKI 耐药机制的深入了解强调了基于基因型的治疗方法的重要性。阐明耐药机制对于靶向创新的治疗方法以及提高 NSCLC 中抗癌方案的疗效确实至关重要。
