ER Stress Signaling Promotes the Survival of Cancer "Persister Cells" Tolerant to EGFR Tyrosine Kinase Inhibitors.
ER Stress Signaling Promotes the Survival of Cancer "Persister Cells" Tolerant to EGFR Tyrosine Kinase Inhibitors.
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DOI：
10.1158/0008-5472.can-17-1904
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发表时间：
2018-02-15
期刊：
影响因子：
11.2
通讯作者：
Barbie DA
中科院分区：
文献类型：
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作者：
Terai H;Kitajima S;Potter DS;Matsui Y;Quiceno LG;Chen T;Kim TJ;Rusan M;Thai TC;Piccioni F;Donovan KA;Kwiatkowski N;Hinohara K;Wei G;Gray NS;Fischer ES;Wong KK;Shimamura T;Letai A;Hammerman PS;Barbie DA
对酪氨酸激酶抑制剂（TKI）的耐药性的一个日益被认识的组成部分涉及癌细胞的耐药亚群的持续存在，尽管有效根除了大多数细胞群，但这些癌细胞亚群仍然存活。多个研究小组已经证明，这些耐药持续细胞通过表观遗传状态变化进行转录适应，从而促进细胞存活。由于这种TKI药物耐受模式似乎涉及对特定基因和途径的转录成瘾，我们假设EGFR TKI/转录抑制剂联合治疗的系统功能筛选将产生重要的机制见解和替代药物逃逸途径。因此，我们在用厄洛替尼+THZ 1（CDK 7/12抑制剂）组合疗法处理的EGFR依赖性肺癌PC 9细胞中进行了全基因组CRISPR/Cas9增强子/抑制子筛选，该组合先前显示在这种情况下抑制药物耐受性细胞。正如预期的那样，抑制与转录复合物（EP 300，CREBBP和MED 1）相关的多个基因增强了厄洛替尼/THZ 1的协同作用。出乎意料的是，我们发现几乎每一个组件最近描述的ufmylation途径的协同抑制组。失ufmylation不影响典型的下游EGFR信号传导。相反，该途径的缺乏触发了与STING上调相关的保护性未折叠蛋白反应（UPR），促进促肿瘤发生的炎症信号传导，但也对Bcl-xL具有独特的依赖性。这些数据表明，ufmylation和ER应激的失调包括一个以前未被认识到的TKI药物耐受途径，参与生存信号传导，具有潜在的重要治疗意义。
An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells which survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy,a combination previously shown to suppress drug tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response (UPR) associated with STING upregulation, promoting pro-tumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.