Virus-Tumor Interactome Screen Reveals ER Stress Response Can Reprogram Resistant Cancers for Oncolytic Virus-Triggered Caspase-2 Cell Death
Virus-Tumor Interactome Screen Reveals ER Stress Response Can Reprogram Resistant Cancers for Oncolytic Virus-Triggered Caspase-2 Cell Death
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DOI：
10.1016/j.ccr.2011.09.005
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发表时间：
2011-10-18
期刊：
影响因子：
50.3
通讯作者：
Stojdl, David F.
中科院分区：
文献类型：
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作者：
Mahoney, Douglas J.;Lefebvre, Charles;Stojdl, David F.
为了确定溶瘤病毒治疗的治疗机会，我们进行了全基因组RNAi筛选，以寻找调节弹状病毒溶瘤的宿主因子。我们的筛选揭示了内质网（ER）应激反应途径作为弹状病毒介导的细胞毒性的重要调节剂。进一步的研究揭示了一种非常规的机制，即ER应激反应抑制预处理的癌细胞，使它们对随后的弹状病毒感染诱导的caspase-2依赖性凋亡敏感。重要的是，这种机制是肿瘤细胞特异性的，选择性地将溶瘤病毒的效力提高高达10，000倍。使用IRE 1 α的小分子抑制剂的体内研究显示在耐药肿瘤模型中显著改善的溶瘤功效。我们的研究证明了使用功能基因组学来改善癌症生物治疗剂的概念。
To identify therapeutic opportunities for oncolytic viral therapy, we conducted genome-wide RNAi screens to search for host factors that modulate rhabdoviral oncolysis. Our screens uncovered the endoplasmic reticulum (ER) stress response pathways as important modulators of rhabdovirus-mediated cytotoxicity. Further investigation revealed an unconventional mechanism whereby ER stress response inhibition preconditioned cancer cells, which sensitized them to caspase-2-dependent apoptosis induced by a subsequent rhabdovirus infection. Importantly, this mechanism was tumor cell specific, selectively increasing potency of the oncolytic virus by up to 10,000-fold. In vivo studies using a small molecule inhibitor of IRE1 alpha showed dramatically improved oncolytic efficacy in resistant tumor models. Our study demonstrates proof of concept for using functional genomics to improve biotherapeutic agents for cancer.