Author/Authors :
Mahoney، نويسنده , , Douglas J. and Lefebvre، نويسنده , , Charles and Allan، نويسنده , , Kristina and Brun، نويسنده , , Jan and Sanaei، نويسنده , , Cina A. and Baird، نويسنده , , Stephen L. Pearce، نويسنده , , Nelson and Grِnberg، نويسنده , , Susanna and Wilson، نويسنده , , Brian and Prakesh، نويسنده , , Mikael and Aman، نويسنده , , Ahmed and Isaac، نويسنده , , Methvin and Mamai، نويسنده , , Ahmed and Uehling، نويسنده , , David and Al-Awar، نويسنده , , Rima and Falls، نويسنده , , Theresa and Alain، نويسنده , , Tommy and Stojdl، نويسنده , , David F.، نويسنده ,
Abstract :
Summary
ntify 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.
