Virus-tumor interactome screen reveals ER stress response can reprogram resistant cancers for oncolytic virus-triggered caspase-2 cell death.
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 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.
Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada.
Douglas J
DJ
Mahoney
Charles
C
Lefebvre
Kristina
K
Allan
Jan
J
Brun
Cina A
CA
Sanaei
Stephen
S
Baird
Nelson
N
Pearce
Susanna
S
Grönberg
Brian
B
Wilson
Mikael
M
Prakesh
Ahmed
A
Aman
Methvin
M
Isaac
Ahmed
A
Mamai
David
D
Uehling
Rima
R
Al-Awar
Theresa
T
Falls
Tommy
T
Alain
David F
DF
Stojdl
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053143:Caspase 2 / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000037:antagonists & inhibitors; D005260:Female; D023281:Genomics / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D034622:RNA Interference; D012209:Rhabdoviridae / Q000502:physiology
C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases