Virus-tumor interactome screen reveals ER stress response can reprogram resistant cancers for oncolytic virus-triggered caspase-2 cell death

Cancer Cell. 2011 Oct 18;20(4):443-56. doi: 10.1016/j.ccr.2011.09.005.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Caspase 2 / metabolism
  • Caspase 2 / physiology
  • Cell Line, Tumor
  • Cysteine Endopeptidases / metabolism
  • Cysteine Endopeptidases / physiology
  • Endoplasmic Reticulum / physiology*
  • Endoplasmic Reticulum Stress*
  • Endoribonucleases / antagonists & inhibitors
  • Female
  • Genomics / methods
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology
  • Glioblastoma / virology
  • Humans
  • Mice
  • Mice, Nude
  • Oncolytic Virotherapy / methods
  • Oncolytic Viruses / immunology
  • Oncolytic Viruses / metabolism
  • Oncolytic Viruses / physiology*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / virology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • RNA Interference
  • Rhabdoviridae / physiology

Substances

  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • CASP2 protein, human
  • Caspase 2
  • Cysteine Endopeptidases