Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer
Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer
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Phospho-ERK 是对索拉非尼和 MEK 合成致死药物组合抑制肝癌反应的生物标志物
DOI：
10.1016/j.jhep.2018.07.004
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发表时间：
2018-11-01
影响因子：
25.7
通讯作者：
Bernards, Rene
中科院分区：
文献类型：
--
作者：
Wang, Cun;Jin, Haojie;Bernards, Rene
背景与目的：由于缺乏针对关键依赖性的药物，肝癌的治疗仍然具有挑战性。索拉非尼是一种多激酶抑制剂，被批准作为晚期肝细胞癌患者的标准治疗，但它只能提供有限的生存益处。在这项研究中，我们的目的是确定潜在的组合疗法，以改善临床反应索拉非尼。方法：调查索拉非尼的有限的治疗效果的原因，我们进行了基于CRISPR-Cas9的合成致死筛选，以寻找激酶，其敲除协同索拉非尼。分别采用caspase-3/7凋亡实验和western blot分析索拉非尼和司美替尼对细胞凋亡和磷酸化ERK（p-ERK）的协同作用。使用含有78个肝癌标本的组织微阵列通过免疫化学分析测量p-ERK。结果：我们发现，抑制ERK 2（MAPK 1）的几种肝癌细胞系索拉非尼的敏感性。抑制MEK的药物（MEK 1/2 [MAP 2K 1/2]）或ERK（ERK 1/2 [MAPK 1/3]）激酶通过协同抑制ERK激酶活性，在体外和体内逆转以高水平活性p-ERK为特征的肝癌细胞系亚组中对索拉非尼的无反应性。我们的数据提供了一种治疗肝癌的联合策略，并表明具有高基础p-ERK水平的肿瘤，在大约30%的肝癌中可见，最有可能受益于这种联合治疗。(C)2018年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Treatment of liver cancer remains challenging because of a paucity of drugs that target critical dependencies. Sorafenib is a multikinase inhibitor that is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but it only provides limited survival benefit. In this study we aimed to identify potential combination therapies to improve the clinical response to sorafenib.Methods: To investigate the cause of the limited therapeutic effect of sorafenib, we performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergizes with sorafenib. Synergistic effects of sorafenib and selumetinib on cell apoptosis and phospho-ERK (p-ERK) were analyzed by caspase-3/7 apoptosis assay and western blot, respectively. p-ERK was measured by immunochemical analysis using a tissue microarray containing 78 liver cancer specimens. The in vivo effects of the combination were also measured in two xenograft models.Result: We found that suppression of ERK2 (MAPK1) sensitizes several liver cancer cell lines to sorafenib. Drugs inhibiting the MEK (MEK1/2 [MAP2K1/2]) or ERK (ERK1/2 [ MAPK1/3]) kinases reverse unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active p-ERK, through synergistic inhibition of ERK kinase activity.Conclusion: Our data provide a combination strategy for treating liver cancer and suggest that tumors with high basal p-ERK levels, which are seen in approximately 30% of liver cancers, are most likely to benefit from such combinatorial treatment. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.