Virus-Tumor Interactome Screen Reveals ER Stress Response Can Reprogram Resistant Cancers for Oncolytic Virus-Triggered Caspase-2 Cell Death

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• 作者：Douglas  ; J. Mahoney¹ ;   ; ² ; Charles Lefebvre¹ ;   ; ² ; Kristina Allan¹ ; Jan Brun¹ ;   ; ² ; Cina  ; A. Sanaei¹ ; Stephen Baird¹ ;   ; ² ; Nelson Pearce¹ ; Susanna Grö ; nberg¹ ; Brian Wilson⁵ ; Mikael Prakesh⁵ ; Ahmed Aman⁵ ; Methvin Isaac⁵ ; Ahmed Mamai⁵ ; David Uehling⁵ ; Rima Al-Awar⁵ ; Theresa Falls⁴ ; Tommy Alain⁶ ; David  ; F. Stojdl¹ ;   ; ² ;   ; ³ ;   ; ^{dave@arc.cheo.ca}
• 刊名：Cancer Cell
• 出版年：2011
• 出版时间：18 October 2011
• 年：2011
• 卷：20
• 期：4
• 页码：443-456
• 全文大小：1428 K

文摘

Summary

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¦Á 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.