title: Overcoming cancer cell resistance to VSV oncolysis with JAK1/2 inhibitors.
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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Escobar-Zarate
authors.forename: Y-P
authors.initials: YP
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Suksanpaisan
authors.forename: S J
authors.initials: SJ
authors.lastname: Russell
authors.forename: K-W
authors.initials: KW
authors.lastname: Peng
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000276:immunology / Q000628:therapy* / Q000821:virology*; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009570:Nitriles; D050130:Oncolytic Virotherapy / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication
chemical_list: D016898:Interferon-alpha; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D016899:Interferon-beta; C540383:ruxolitinib; D053613:Janus Kinase 1; D053614:Janus Kinase 2
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