warfarin and Carcinoma--Pancreatic-Ductal

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Axl Receptor Tyrosine Kinase; Carcinoma, Pancreatic Ductal; Cell Division; Cell Line, Tumor; Cell Movement; Deoxycytidine; Disease Progression; Drug Synergism; Epithelial-Mesenchymal Transition; Female; Gemcitabine; Gene Knockdown Techniques; Humans; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Pancreatic Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; RNA, Small Interfering; Signal Transduction; Specific Pathogen-Free Organisms; Warfarin; Xenograft Model Antitumor Assays