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

ABSTRACT: 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.

SUBMITTER: Wong B

PROVIDER: S-EPMC9065483 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Wong Boaz B Bergeron Anabel A Alluqmani Nouf N Maznyi Glib G Chen Andrew A Arulanandam Rozanne R Diallo Jean-Simon JS

Molecular therapy oncolytics 20220419

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 ...[more]

PMID: 35572196

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Project description:BackgroundAttenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however.MethodsWe performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX). Using a unique gene signature we identified, we generated a diagonal linear discriminant analysis (DLDA) classification algorithm to predict MV responders and nonresponders, which was validated in additional randomly selected GBM and ovarian cancer PDX and 10 GBM patients treated with MV in a phase I trial. GBM PDX lines were also treated with the US Food and Drug Administration-approved JAK inhibitor, ruxolitinib, for 48 hours prior to MV infection and virus production, STAT1/3 signaling and interferon stimulated gene expression was assessed. All statistical tests were two-sided.ResultsConstitutive interferon pathway activation, as reflected in the DLDA algorithm, was identified as the key determinant for MV replication, independent of virus receptor expression, in MV-permissive and -resistant GBM PDXs. Using these lines as the training data for the DLDA algorithm, we confirmed the accuracy of our algorithm in predicting MV response in randomly selected GBM PDX ovarian cancer PDXs. Using the DLDA prediction algorithm, we demonstrate that virus replication in patient tumors is inversely correlated with expression of this resistance gene signature (ρ = -0.717, P = .03). In vitro inhibition of the interferon response pathway with the JAK inhibitor ruxolitinib was able to overcome resistance and increase virus production (1000-fold, P = .03) in GBM PDX lines.ConclusionsThese findings document a key mechanism of tumor resistance to oncolytic MV therapy and describe for the first time the development of a prediction algorithm to preselect for oncolytic treatment or combinatorial strategies.

Dataset Information

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

Publications

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

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