Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells.
Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells.
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DOI：
10.1038/ncomms10690
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发表时间：
2016-02-19
影响因子：
16.6
通讯作者：
Altschuler SJ
中科院分区：
文献类型：
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作者：
Ramirez M;Rajaram S;Steininger RJ;Osipchuk D;Roth MA;Morinishi LS;Evans L;Ji W;Hsu CH;Thurley K;Wei S;Zhou A;Koduru PR;Posner BA;Wu LF;Altschuler SJ
传统上，癌症治疗的重点是消灭快速增长的细胞群。然而，越来越多的证据表明，一小部分癌细胞亚群可以通过进入一种可以忽略不计的“持续”生长状态来逃避强大的选择性药物压力。这种耐药状态被假设为最终获得真正耐药机制的初始策略的一部分。然而，耐药机制的多样性，可以扩大从一个持续的瓶颈是未知的。在这里，我们比较了来自单个egfr成瘾肺癌细胞的持久衍生的厄洛替尼耐药菌落。我们发现，结合大规模药物筛选和全外显子组测序，我们的厄洛替尼耐药菌落获得了多种耐药机制，包括最常见的临床耐药机制。因此，耐药持续状态并不限制-甚至可能为异质耐药机制的出现提供潜在的细胞库。在最初的药物治疗中存活下来的癌细胞可以在药物存在的情况下持续存在。在这里，作者产生了对EGFR酪氨酸激酶抑制剂厄洛替尼耐药的持久性细胞，并通过单细胞分析表明，多种机制导致了耐药的持久性状态。
Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. Yet, an increasing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a ‘persister' state of negligible growth. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here we compare persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We find, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit—and may even provide a latent reservoir of cells for—the emergence of heterogeneous drug-resistance mechanisms. Cancer cells that survive initial drug treatment can persist in the presence of drugs. Here, the authors generate persister cells that are resistant to the EGFR tyrosine kinase inhibitor erlotinib and show by single cell analysis that multiple mechanism give rise to the drug-resistant persister state.