In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer.
In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer.
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DOI：
10.1038/nm.3679
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发表时间：
2014-10
期刊：
影响因子：
82.9
通讯作者：
Zender L
中科院分区：
文献类型：
--
作者：
Rudalska R;Dauch D;Longerich T;McJunkin K;Wuestefeld T;Kang TW;Hohmeyer A;Pesic M;Leibold J;von Thun A;Schirmacher P;Zuber J;Weiss KH;Powers S;Malek NP;Eilers M;Sipos B;Lowe SW;Geffers R;Laufer S;Zender L
在实体瘤中，在使用细胞毒性药物或分子靶向疗法治疗时不可避免地会产生治疗耐药性。在这里，我们描述了一种能够直接在小鼠肝细胞癌 (HCC) 体内进行混合 shRNA 筛选的系统，以识别可能与治疗耐药相关的基因。使用针对位于人类 HCC 局部基因组扩增内的基因的聚焦 shRNA 文库，我们筛选了其抑制可提高多激酶抑制剂索拉非尼治疗效果的基因。研究发现，shRNA 介导的 Mapk14 (p38α) 沉默和药理学沉默均可使小鼠 HCC 对索拉非尼治疗敏感，并通过消除 Mapk14 依赖性的 Mek-Erk 和 Atf2 信号传导激活来延长生存期。 Mapk14-Atf2 信号传导升高预示人类 HCC 对索拉非尼治疗的反应不佳，并且表达 p-Mapk14 的 HCC 细胞对索拉非尼的耐药性可以通过沉默 Mapk14 来恢复。我们的结果表明，索拉非尼和 Mapk14 阻断的组合是克服人类 HCC 治疗耐药性的一种有前途的方法。
In solid tumors, resistance to therapy inevitably develops upon treatment with cytotoxic drugs or molecularly targeted therapies. Here, we describe a system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas (HCC) in vivo to identify genes likely to be involved in therapy resistance. Using a focused shRNA library targeting genes located within focal genomic amplifications of human HCC, we screened for genes whose inhibition increased the therapeutic efficacy of the multikinase inhibitor sorafenib. Both shRNA-mediated and pharmacological silencing of Mapk14 (p38α) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14-dependent activation of Mek-Erk and Atf2 signaling. Elevated Mapk14-Atf2 signaling predicted poor response to sorafenib therapy in human HCC, and sorafenib resistance of p-Mapk14-expressing HCC cells could be reverted by silencing Mapk14. Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.