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Overcoming cancer cell resistance to VSV oncolysis with JAK1/2 inhibitors

Cancer Gene Therapy volume 20, pages 582–589 (2013)Cite this article

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Abstract

Oncolytic vesicular stomatitis virus (VSV) has potent antitumor activity but some cancer cells are resistant to VSV killing, either constitutively or due to type I interferon (IFN) inducing an antiviral state in the cells. Here, we evaluated VSV oncolysis of a panel of human head and neck cancer cells and showed that VSV resistance in SCC25 and SCC15 cells could be reversed with Janus kinase (JAK) 1/2 inhibitors (JAK inhibitor I and ruxolitinib). Pre-treatment of cells with JAK1/2 inhibitors before or in conjunction with VSV enhanced viral infection, spread and progeny yield (100- to 1000-fold increase). In contrast, inhibitors of histone deacetylase (LBH589), phosphatidylinositol 3-kinase (GDC-0941, LY294002), mammalian target of rapamycin (rapamycin) or signal transducer and activator of transcription 3 (STAT3 inhibitor VII) were ineffective. Compared with VSV-sensitive SW579 cells, IFNα/β responsive antiviral genes (IRF-9, IRF-7, OAS1 but not MxA) are constitutively expressed in SCC25 cells. Pretreatment with JAK inhibitors reduced mRNA levels of these genes, increasing VSV expression in the cells. Interestingly, 1 h of drug exposure was sufficient to reverse SCC25 resistance to VSV and was still effective if virus was added 24 h later. Overall, we show here that JAK inhibitor I and ruxolitinib (Jakafi) can reverse resistance to VSV, supporting the rationale to incorporate JAK1/2 inhibitors in future VSV virotherapy trials.

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Acknowledgements

We are grateful to funding support from Mayo Foundation.

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Authors and Affiliations

  1. Department of Molecular Medicine, Mayo Clinic, MN, Rochester, USA

    D Escobar-Zarate, Y-P Liu, L Suksanpaisan, S J Russell & K-W Peng

  2. Division of Hematology, Mayo Clinic, MN, Rochester, USA

    S J Russell

  3. Department of Obstetrics and Gynecology, Mayo Clinic, MN, Rochester, USA

    K-W Peng

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  1. D Escobar-Zarate
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Correspondence to K-W Peng.

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Competing interests

SJR and KWP have financial interests in Omnis Pharma, an oncolytic VSV company.

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Escobar-Zarate, D., Liu, YP., Suksanpaisan, L. et al. Overcoming cancer cell resistance to VSV oncolysis with JAK1/2 inhibitors. Cancer Gene Ther 20, 582–589 (2013). https://doi.org/10.1038/cgt.2013.55

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