1. Virus-Tumor Interactome Screen Reveals ER Stress Response Can Reprogram Resistant Cancers for Oncolytic Virus-Triggered Caspase-2 Cell Death
- Author
-
Ahmed Mamai, Susanna Grönberg, Rima Al-awar, Tommy Alain, Stephen Baird, David Uehling, Douglas J. Mahoney, Jan Brun, David F. Stojdl, Methvin Isaac, Ahmed Aman, Charles Lefebvre, Mikael Prakesh, Theresa Falls, Cina A. Sanaei, Brian J. Wilson, Nelson Pearce, and Kristina J. Allan
- Subjects
Cancer Research ,Programmed cell death ,Caspase 2 ,Mice, Nude ,Apoptosis ,Protein Serine-Threonine Kinases ,Biology ,Endoplasmic Reticulum ,Virus ,Mice ,RNA interference ,Cell Line, Tumor ,Endoribonucleases ,Animals ,Humans ,Oncolytic Virotherapy ,Ovarian Neoplasms ,Endoplasmic reticulum ,Genomics ,Cell Biology ,Endoplasmic Reticulum Stress ,Virology ,Oncolytic virus ,Cysteine Endopeptidases ,Oncolytic Viruses ,Oncology ,Cancer cell ,Cancer research ,biology.protein ,Female ,RNA Interference ,Rhabdoviridae ,Glioblastoma - Abstract
SummaryTo 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 IRE1α 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.
- Published
- 2011
- Full Text
- View/download PDF