Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Rozanne Arulanandam, Cory Batenchuk, Oliver Varette, Chadi Zakaria, Vanessa Garcia, Nicole E. Forbes, Colin Davis, Ramya Krishnan, Raunak Karmacharya, Julie Cox, Anisha Sinha, Andrew Babawy, Katherine Waite, Erica Weinstein, Theresa Falls, Andrew Chen, Jeff Hamill, Naomi De Silva, David P. Conrad, Harold Atkins, Kenneth Garson, Carolina Ilkow, Mads Kærn, Barbara Vanderhyden, Nahum Sonenberg, Tommy Alain, Fabrice Le Boeuf, John C. Bell and Jean-Simon Diallo ()
Additional contact information
Rozanne Arulanandam: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Cory Batenchuk: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Oliver Varette: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Chadi Zakaria: Goodman Cancer Center, McGill University
Vanessa Garcia: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Nicole E. Forbes: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Colin Davis: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Ramya Krishnan: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Raunak Karmacharya: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Julie Cox: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Anisha Sinha: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Andrew Babawy: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Katherine Waite: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Erica Weinstein: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Theresa Falls: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Andrew Chen: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Jeff Hamill: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Naomi De Silva: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
David P. Conrad: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Harold Atkins: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Kenneth Garson: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Carolina Ilkow: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Mads Kærn: Ottawa Institute of Systems Biology, University of Ottawa
Barbara Vanderhyden: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Nahum Sonenberg: Goodman Cancer Center, McGill University
Tommy Alain: Children’s Hospital of Eastern Ontario Research Institute
Fabrice Le Boeuf: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
John C. Bell: Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Jean-Simon Diallo: Center for Innovative Cancer Research, Ottawa Hospital Research Institute

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

Date: 2015
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DOI: 10.1038/ncomms7410

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