A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers.
A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers.
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DOI：
10.1186/s13073-018-0600-z
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发表时间：
2018-11-27
期刊：
影响因子：
12.3
通讯作者：
Bernards R
中科院分区：
文献类型：
--
作者：
Šuštić T;van Wageningen S;Bosdriesz E;Reid RJD;Dittmar J;Lieftink C;Beijersbergen RL;Wessels LFA;Rothstein R;Bernards R
KRAS基因突变在人类癌症中很常见，但仍然缺乏针对这些癌症的有效靶向治疗。对KRAS下游的MEK激酶进行药物治疗的尝试在临床试验中取得的成功有限。了解KRAS驱动的癌症的特定基因组脆弱性可能会发现新的患者定制治疗方案。我们首先在酵母中寻找合成致死(SL)与突变RAS的遗传相互作用，最终目的是确定新的癌症特异性治疗靶点。我们的方法使用选择性倍体消融，这使得在酵母基因中断库中复制癌症特异性基因表达变化成为可能。其次，我们在KRAS突变的人结肠癌细胞中使用了基于CRISPR/Cas9的全基因组遗传筛查，以了解在酵母中发现的合成致命相互作用与人类细胞中的RAS下游信号之间的机制联系。我们确定内质网(ER)应激感受器IRE1的丢失是酵母中激活的RAS突变体的合成致死。在KRAS突变的结直肠癌细胞系中，基因消融人类IRE1，ERN1的同源基因不会影响生长，但会对MEK抑制敏感。然而，ERN1激酶抑制剂未能显示出与MEK抑制的协同作用，这表明ERN1的非激酶功能赋予MEK抑制剂耐药性。为了研究ERN1如何调节MEK抑制剂的反应，我们在ERN1基因敲除KRAS突变的结肠癌细胞中进行了基因筛选，以确定其失活导致对MEK抑制具有抵抗力的基因。这一遗传筛查发现了Jun氨基末端激酶(JNK)/Jun信号的多个负调控因子。一直以来，针对JNK/MAPK8或TAK1/MAP3K7的化合物将信号从ERN1传递到Jun，显示出与MEK抑制的协同作用。我们发现ERN1-JNK-Jun通路是KRAS突变结肠癌中MEK抑制反应的一种新的调节因子。多条信号通路可以激活Jun的概念可能解释了为什么KRAS突变的肿瘤细胞传统上被视为对MEK抑制剂治疗高度耐药。我们的发现强调了开发针对Jun激活蛋白激酶的新疗法的必要性，TAK1和JNK，以使KRAS突变的癌细胞对MEK抑制剂敏感。本文的在线版本(10.1186/s13073-0180600-z)包含向授权用户提供的补充材料。
Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical trials. Understanding the specific genomic vulnerabilities of KRAS-driven cancers may uncover novel patient-tailored treatment options. We first searched for synthetic lethal (SL) genetic interactions with mutant RAS in yeast with the ultimate aim to identify novel cancer-specific targets for therapy. Our method used selective ploidy ablation, which enables replication of cancer-specific gene expression changes in the yeast gene disruption library. Second, we used a genome-wide CRISPR/Cas9-based genetic screen in KRAS mutant human colon cancer cells to understand the mechanistic connection between the synthetic lethal interaction discovered in yeast and downstream RAS signaling in human cells. We identify loss of the endoplasmic reticulum (ER) stress sensor IRE1 as synthetic lethal with activated RAS mutants in yeast. In KRAS mutant colorectal cancer cell lines, genetic ablation of the human ortholog of IRE1, ERN1, does not affect growth but sensitizes to MEK inhibition. However, an ERN1 kinase inhibitor failed to show synergy with MEK inhibition, suggesting that a non-kinase function of ERN1 confers MEK inhibitor resistance. To investigate how ERN1 modulates MEK inhibitor responses, we performed genetic screens in ERN1 knockout KRAS mutant colon cancer cells to identify genes whose inactivation confers resistance to MEK inhibition. This genetic screen identified multiple negative regulators of JUN N-terminal kinase (JNK) /JUN signaling. Consistently, compounds targeting JNK/MAPK8 or TAK1/MAP3K7, which relay signals from ERN1 to JUN, display synergy with MEK inhibition. We identify the ERN1-JNK-JUN pathway as a novel regulator of MEK inhibitor response in KRAS mutant colon cancer. The notion that multiple signaling pathways can activate JUN may explain why KRAS mutant tumor cells are traditionally seen as highly refractory to MEK inhibitor therapy. Our findings emphasize the need for the development of new therapeutics targeting JUN activating kinases, TAK1 and JNK, to sensitize KRAS mutant cancer cells to MEK inhibitors. The online version of this article (10.1186/s13073-018-0600-z) contains supplementary material, which is available to authorized users.
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DOI：
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