Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target
Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target
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DOI：
10.1158/1078-0432.ccr-18-0304
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发表时间：
2018-11-15
影响因子：
11.5
通讯作者：
Faber, Anthony C.
中科院分区：
文献类型：
--
作者：
Song, Kyung-A;Hosono, Yasuyuki;Faber, Anthony C.
目的：EGFR抑制剂（EGFRi）对EGFR突变型肺癌有效。然而，这些药物的疗效会因耐药细胞的生长而减弱，耐药细胞通常是由EGFR中继发性获得性突变T790M驱动的。我们最近证明T790M可以在治疗期间重新出现；因此，阻止耐药性的一种潜在的治疗策略是在获得像T790M这样的继发性突变之前识别和消除这些细胞[称为耐药细胞（DTC）]。实验设计：我们已经在egfr突变肺癌细胞系中开发了针对EGFRi的dtc。dtc的后续分析包括RNA-seq、高含量显微镜和蛋白质翻译分析。基于这些结果，我们在体内测试了MCL-1 BH3模拟物与EGFR抑制剂联合消除dtc和缩小EGFR突变肺癌肿瘤的能力。结果：我们证明存活的egfr突变肺癌细胞对短期EGFRi治疗有上调抗凋亡蛋白MCL-1的反应。在机制上，dtc经历蛋白质生物合成富集，导致mtorc1介导的MCL-1 mRNA翻译增加，揭示了肺癌细胞适应凋亡诱导激酶抑制剂短期压力的新机制。此外，MCL-1是控制早期egfr突变dtc到EGFRi出现的关键分子，我们证明它可以在体外和体内有效地与临床新出现的MCL-1抑制剂共同靶向。结论：总之，这些数据表明，这种新的治疗组合可能延迟继发性突变的获得，从而延长治疗效果。(c) 2018年aacr。
Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M. We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790M.Experimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivo.Results: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivo.Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. (C) 2018 AACR.