Tumors driven by RAS signaling harbor a natural vulnerability to oncolytic virus M1.
Tumors driven by RAS signaling harbor a natural vulnerability to oncolytic virus M1.
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由 RAS 信号驱动的肿瘤对溶瘤病毒 M1 具有天然的脆弱性。
DOI：
10.1002/1878-0261.12820
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发表时间：
2020-12
影响因子：
6.6
通讯作者：
Liang J
中科院分区：
文献类型：
--
作者：
Cai J;Lin K;Cai W;Lin Y;Liu X;Guo L;Zhang J;Xu W;Lin Z;Wong CW;Sander M;Hu J;Yan G;Zhu W;Liang J
RAS/RAF/MAPK/p-ERK信号转导通过抑制P21和随后抑制细胞周期蛋白依赖性激酶2（CDK 2）促进M1病毒的复制和溶瘤作用。索拉非尼或U 0126抑制RAS/RAF/MAPK/p-ERK信号传导可抑制M1的溶瘤作用。敲除p21可增强M1的作用，而过表达p21可抑制其作用。K 03861抑制CDK 2可减弱M1的作用。 溶瘤病毒是有效的抗癌剂，其在癌细胞内复制并杀死癌细胞而不是正常细胞，并且它们的选择性在很大程度上由致癌突变决定。M1是一种新型溶瘤病毒株，已被证明可靶向癌细胞，但其癌症选择性与致癌信号通路之间的关系尚不清楚。在这里，我们报告RAS突变促进了M1在癌症中的复制和溶瘤作用，我们进一步提供了RAS/RAF/MEK信号轴抑制M1感染和随后的细胞病变作用的证据。转录组分析显示，RAS信号的抑制上调I型干扰素抗病毒反应，进一步的RNA干扰筛选确定CDKN 1A为抑制病毒感染的关键下游因子。功能获得和丧失实验证实，CDKN 1A抑制M1病毒的复制和溶瘤作用。随后的TCGA数据挖掘和组织微阵列（TMA）分析显示，CDKN 1A在人类癌症中普遍缺乏，这表明M1具有广泛的临床应用前景。我们的报告表明，病毒疗法对于治疗不可治疗的RAS驱动的癌症是可行的，并为个性化癌症治疗提供了可靠的生物标志物。
RAS/RAF/MAPK/p‐ERK signaling promotes the replication and oncolytic effect of M1 virus via inhibiting P21 and subsequent suppression of Cyclin‐dependent kinase 2 (CDK2). Inhibition of RAS/RAF/MAPK/p‐ERK signaling by sorafenib or U0126 suppresses the oncolytic effect of M1. Knockout of p21 enhances the effect of M1, while overexpression of p21 inhibits it. Inhibition of CDK2 by K03861 attenuates the efficacy of M1. Oncolytic viruses are potent anticancer agents that replicate within and kill cancer cells rather than normal cells, and their selectivity is largely determined by oncogenic mutations. M1, a novel oncolytic virus strain, has been shown to target cancer cells, but the relationship between its cancer selectivity and oncogenic signaling pathways is poorly understood. Here, we report that RAS mutation promotes the replication and oncolytic effect of M1 in cancer, and we further provide evidence that the inhibition of the RAS/RAF/MEK signaling axis suppresses M1 infection and the subsequent cytopathic effects. Transcriptome analysis revealed that the inhibition of RAS signaling upregulates the type I interferon antiviral response, and further RNA interference screen identified CDKN1A as a key downstream factor that inhibits viral infection. Gain‐ and loss‐of‐function experiments confirmed that CDKN1A inhibited the replication and oncolytic effect of M1 virus. Subsequent TCGA data mining and tissue microarray (TMA) analysis revealed that CDKN1A is commonly deficient in human cancers, suggesting extensive clinical application prospects for M1. Our report indicates that virotherapy is feasible for treating undruggable RAS‐driven cancers and provides reliable biomarkers for personalized cancer therapy.
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DOI：
10.1038/mt.2011.276
发表时间：
2012-04
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
21.3
作者：
Farassati, F;Yang, AD;Lee, PWK
通讯作者：
Lee, PWK
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
6.7
作者：
Baril M;Es-Saad S;Chatel-Chaix L;Fink K;Pham T;Raymond VA;Audette K;Guenier AS;Duchaine J;Servant M;Bilodeau M;Cohen E;Grandvaux N;Lamarre D
通讯作者：
Lamarre D