LKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors
LKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors
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DOI：
10.1016/j.jtho.2019.10.009
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发表时间：
2020-03-01
影响因子：
20.4
通讯作者：
Marabese, Mirko
中科院分区：
文献类型：
--
作者：
Caiola, Elisa;Iezzi, Alice;Marabese, Mirko
简介：丝氨酸/苏氨酸激酶 11 (LKB1/STK11) 是 NSCLC 中突变最严重的基因之一，约占 NSCLC 病例的三分之一，并且在大约一半的 KRAS 突变 NSCLC 中其活性受损。目前，这些患者无法从任何特定治疗中受益。方法：通过CRISPR/Cas9技术，我们系统地删除了野生型（WT）和KRAS突变的人类NSCLC细胞中的LKB1。通过将这些同基因系统与基因工程小鼠模型一起使用，我们在体外和体内研究了细胞对 ERK 抑制剂的反应。结果：在此处使用的所有系统中，LKB1 的丢失造成了脆弱性，并使这些细胞在体外和体内对 ERK 抑制剂特别敏感。表达 WT LKB1 的相同细胞对这些药物的反应很差。在分子水平上，在LKB1缺失的情况下，ERK抑制剂可显着抑制p90核糖体S6激酶的激活，进而消除S6蛋白的激活，促进细胞毒作用。结论：本研究表明ERK抑制剂对LKB1和LKB1/KRAS突变的肿瘤有效，从而为该疾病提供了治疗策略。 预后不良的患者亚组。由于 ERK 抑制剂已进入临床开发阶段，因此我们的研究结果可以轻松转化为临床。重要的是，表达 WT LKB1 的细胞缺乏效果，预示着用 ERK 抑制剂治疗 LKB1 突变肿瘤应该具有良好的毒性特征。 (C) 2019 年国际肺癌研究协会。由爱思唯尔公司出版。保留所有权利。
Introduction: Serine/threonine kinase 11 (LKB1/STK11) is one of the most mutated genes in NSCLC accounting for approximately one-third of cases and its activity is impaired in approximately half of KRAS-mutated NSCLC. At present, these patients cannot benefit from any specific therapy.Methods: Through CRISPR/Cas9 technology, we systematically deleted LKB1 in both wild-type (WT) and KRAS-mutated human NSCLC cells. By using these isogenic systems together with genetically engineered mouse models we investigated the cell response to ERK inhibitors both in vitro and in vivo.Results: In all the systems used here, the loss of LKB1 creates vulnerability and renders these cells particularly sensitive to ERK inhibitors both in vitro and in vivo. The same cells expressing a WT LKB1 poorly respond to these drugs. At the molecular level, in the absence of LKB1, ERK inhibitors induced a marked inhibition of p90 ribosomal S6 kinase activation, which in turn abolished S6 protein activation, promoting the cytotoxic effect.Conclusions: This work shows that ERK inhibitors are effective in LKB1 and LKB1/KRAS-mutated tumors, thus offering a therapeutic strategy for this prognostically unfavorable subgroup of patients. Because ERK inhibitors are already in clinical development, our findings could be easily translatable to the clinic. Importantly, the lack of effect in cells expressing WT LKB1, predicts that treatment of LKB1-mutated tumors with ERK inhibitors should have a favorable toxicity profile. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.