Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis

Cancer Res. 2015 Sep 15;75(18):3699-705. doi: 10.1158/0008-5472.CAN-14-2887-T. Epub 2015 Jul 23.

Abstract

Repurposing "old" drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Disease Progression
  • Drug Synergism
  • Epithelial-Mesenchymal Transition / drug effects*
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • RNA, Small Interfering / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Signal Transduction / drug effects
  • Specific Pathogen-Free Organisms
  • Warfarin / administration & dosage
  • Warfarin / pharmacology*
  • Warfarin / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • growth arrest-specific protein 6
  • Deoxycytidine
  • Warfarin
  • gemcitabine
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase