The JAK2/STAT5 signaling pathway as a potential therapeutic target in canine mastocytoma

Vet Comp Oncol. 2018 Mar;16(1):55-68. doi: 10.1111/vco.12311. Epub 2017 Apr 11.

Abstract

Background: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma.

Materials and methods: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1.

Results: Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells.

Conclusion: The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma.

Keywords: JAK2; KIT; STAT5; canine mastocytoma; targeted drugs.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dog Diseases / drug therapy
  • Dog Diseases / metabolism*
  • Dogs
  • Flow Cytometry / veterinary
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism*
  • Mastocytoma / drug therapy
  • Mastocytoma / metabolism
  • Mastocytoma / veterinary*
  • Norbornanes / pharmacology
  • Pimozide / pharmacology
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Pyrrolidines / pharmacology
  • STAT5 Transcription Factor / antagonists & inhibitors
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Stilbenes / pharmacology
  • Sulfonamides / pharmacology

Substances

  • AZD 1480
  • INCB018424
  • MSC1992371A
  • Norbornanes
  • Pyrazoles
  • Pyrimidines
  • Pyrrolidines
  • STAT5 Transcription Factor
  • Stilbenes
  • Sulfonamides
  • Pimozide
  • 3,3',4,5'-tetrahydroxystilbene
  • Fedratinib
  • Janus Kinase 2