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

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

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)582-589
Number of pages8
JournalCancer Gene Therapy
Volume20
Issue number10
DOIs
StatePublished - Oct 2013

Keywords

  • Antiviral genes
  • Interferon
  • JAK inhibitor I
  • Oncolytic VSV
  • Ruxolitinib
  • SCCHN

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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