Yu Helena A, Riely Gregory J, Lovly Christine M
Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, New York.
Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Clin Cancer Res. 2014 Dec 1;20(23):5898-907. doi: 10.1158/1078-0432.CCR-13-2437. Epub 2014 Oct 10.
Patients with EGFR-mutant lung cancer derive significant therapeutic benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance is an inevitable consequence of this treatment strategy, with a broad variety of resistance mechanisms including acquired EGFR mutations (e.g., T790M) and activation of bypass signaling pathways, such as MET and HER2. Several therapeutic strategies hypothesized to delay or overcome resistance have been tested in clinical trials, including "next-generation" EGFR TKIs and rational combinations of targeted agents. However, to date, there are no FDA-approved therapies for patients with acquired resistance to first-line EGFR TKI therapy. There remains a critical need for more effective and better tailored treatments in this setting to match treatments to the individual patient and specific resistance mechanism at hand. In this review, we discuss known mechanisms of resistance to first-line EGFR TKI therapy and describe previous and ongoing strategies to overcome resistance.
表皮生长因子受体（EGFR）突变的肺癌患者可从EGFR酪氨酸激酶抑制剂（TKI）治疗中获得显著的治疗益处。不幸的是，获得性耐药是这种治疗策略不可避免的结果，其耐药机制多种多样，包括获得性EGFR突变（如T790M）以及旁路信号通路（如MET和HER2）的激活。几种被认为可以延缓或克服耐药的治疗策略已在临床试验中进行了测试，包括“下一代”EGFR TKI和靶向药物的合理联合。然而，迄今为止，对于一线EGFR TKI治疗获得性耐药的患者，尚无美国食品药品监督管理局（FDA）批准的治疗方法。在这种情况下，仍然迫切需要更有效、更具针对性的治疗方法，以便根据个体患者和具体耐药机制来匹配治疗方案。在本综述中，我们讨论了一线EGFR TKI治疗的已知耐药机制，并描述了以往和正在进行的克服耐药的策略。
