Dependency of EGFR activation in vanadium-based sensitization to oncolytic virotherapy

Molecular Therapy: Oncolytics

Rozanne Arulanandam¹  Glib Maznyi¹  Anabel Bergeron¹  Boaz Wong²  Andrew Chen²  Jean-Simon Diallo²  Nouf Alluqmani² 

[1] Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada;

关键词: EGFR;    oncolytic virotherapy;    vanadium;    interferon;    cell signaling;    viral sensitization;   

DOI  :  

来源: DOAJ

【 摘 要 】

Oncolytic virotherapy is a clinically validated approach to treat cancers such as melanoma; however, tumor resistance to virus makes its efficacy variable. Compounds such as sodium orthovanadate (vanadate) can overcome viral resistance and synergize with RNA-based oncolytic viruses. In this study, we explored the basis of vanadate mode of action and identified key cellular components in vanadate’s oncolytic virus-enhancing mechanism using a high-throughput kinase inhibitor screen. We found that several kinase inhibitors affecting signaling downstream of the epidermal growth factor receptor (EGFR) pathway abrogated the oncolytic virus-enhancing effects of vanadate. EGFR pathway inhibitors such as gefitinib negated vanadate-associated changes in the phosphorylation and localization of STAT1/2 as well as NF-κB signaling. Moreover, gefitinib treatment could abrogate the viral sensitizing response of vanadium compounds in vivo. Together, we demonstrate that EGFR signaling plays an integral role in vanadium viral sensitization and that pharmacological EGFR blockade can counteract vanadium/oncolytic virus combination therapy.

【 授权许可】

Unknown