Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1

Virology. 2015 Nov;485:340-54. doi: 10.1016/j.virol.2015.08.003. Epub 2015 Aug 29.

Abstract

Vesicular stomatitis virus (VSV) is an effective oncolytic virus against most human pancreatic ductal adenocarcinoma (PDAC) cell lines. However, some PDAC cell lines are highly resistant to oncolytic VSV-ΔM51 infection. To better understand the mechanism of resistance, we tested a panel of 16 small molecule inhibitors of different cellular signaling pathways, and identified TPCA-1 (IKK-β inhibitor) and ruxolitinib (JAK1/2 inhibitor), as strong enhancers of VSV-ΔM51 replication and virus-mediated oncolysis in all VSV-resistant PDAC cell lines. Both TPCA-1 and ruxolitinib similarly inhibited STAT1 and STAT2 phosphorylation and decreased expression of antiviral genes MxA and OAS. Moreover, an in situ kinase assay provided biochemical evidence that TPCA-1 directly inhibits JAK1 kinase activity. Together, our data demonstrate that TPCA-1 is a unique dual inhibitor of IKK-β and JAK1 kinase, and provide a new evidence that upregulated type I interferon signaling plays a major role in resistance of pancreatic cancer cells to oncolytic viruses.

Keywords: IKK inhibitor; Interferon signaling; Janus kinase (JAK); NF-kappa B (NF-κB); Oncolytic virus; Pancreatic cancer; Ruxolitinib; TPCA-1; Vesicular stomatitis virus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / pharmacology*
  • Cell Line, Tumor
  • Cytopathogenic Effect, Viral / drug effects
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • Interferon Type I / metabolism
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / metabolism
  • Myxovirus Resistance Proteins / genetics
  • Oncolytic Viruses / drug effects
  • Oncolytic Viruses / physiology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / virology*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology
  • STAT Transcription Factors / metabolism
  • Sendai virus / drug effects
  • Sendai virus / physiology
  • Signal Transduction / drug effects
  • Thiophenes / pharmacology*
  • Vesicular stomatitis Indiana virus / drug effects
  • Vesicular stomatitis Indiana virus / physiology*
  • Virus Replication / drug effects

Substances

  • Amides
  • INCB018424
  • Interferon Type I
  • MX1 protein, human
  • Myxovirus Resistance Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • STAT Transcription Factors
  • Thiophenes
  • 2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide
  • Janus Kinases
  • I-kappa B Kinase