Inhibition of Pyruvate Dehydrogenase Kinase Enhances the Antitumor Efficacy of Oncolytic Reovirus
Authors: Michael A Giacomantonio
Gopal P Pathak
Youra Kim
Shashi Gujar
John Patrick Murphy
Namit Holay
Prathyusha Konda
Derek R Clements
Yassine El Hiani
Barry E Kennedy
Journal: Cancer Research (2019)
Discipline: CLINICAL MEDICINE
Keywords: Oncolytic viruses; cancer cell metabolism; susceptibility; metabolic perturbations; mass spectrometry
Affiliations: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada., Department Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada., Department Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada., Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. ., Department Biology, Dalhousie University, Halifax, Nova Scotia, Canada., Centre for Innovative and Collaborative Health Systems Research, IWK Health Centre, Halifax, Nova Scotia, Canada.

Abstract:  Oncolytic viruses (OV) such as reovirus preferentially infect and kill cancer cells. Thus, the mechanisms that dictate the susceptibility of cancer cells to OV-induced cytotoxicity hold the key to their success in clinics. Here, we investigated whether cancer cell metabolism defines its susceptibility to OV and if OV-induced metabolic perturbations can be therapeutically targeted. Using mass spectrometry-based metabolomics and extracellular flux analysis on a panel of cancer cell lines with varying degrees of susceptibility to reovirus, we found that OV-induced changes in central energy metabolism, pyruvate metabolism, and oxidative stress correlate with their susceptibility to reovirus. In particular, reovirus infection accentuated Warburg-like metabolic perturbations in cell lines relatively resistant to oncolysis. These metabolic changes were facilitated by oxidative stress-induced inhibitory phosphorylation of pyruvate dehydrogenase (PDH) that impaired the routing of pyruvate into the tricarboxylic acid cycle and established a metabolic state unsupportive of OV replication. From the therapeutic perspective, reactivation of PDH in cancer cells that were weakly sensitive for reovirus, either through PDH kinase (PDK) inhibitors dichloroacetate and AZD7545 or short hairpin RNA-specific depletion of PDK1, enhanced the efficacy of reovirus-induced oncolysis in vitro and in vivo. These findings identify targeted metabolic reprogramming as a possible combination strategy to enhance the antitumor effects of OV in clinics. SIGNIFICANCE: This study proposes targeted metabolic reprogramming as a valid combinatorial strategy to enhance the translational efficacy of oncolytic virus-based cancer therapies.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/15/3824/F1.large.jpg. 

Retracted: No

PubPeer comments:
 The authors show no reovirus infection of tramp c1 cells in their supplementary data but show a very high cell death after virus treatment. Why are the cells going through cell death if they not being infected by virus? Previous publication from the same group showed high infectivity of prostate cancer cell line Tramp C1 with reovirus (PMID: 21245852). Does this virus infect or not infect prostate cancer cell line tramp c1? It is unclear. ,