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1.
Cancer Res ; 78(1): 246-255, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29180468

ABSTRACT

Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDAC), where it coordinately mediates immune evasion and drug resistance. Here, we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDAC cells in vitro and enhance gemcitibine efficacy in vivo Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response, and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDAC patients.Significance: These results establish a preclinical mechanistic rationale for the clinical development of AXL inhibitors to improve the treatment of PDAC patients. Cancer Res; 78(1); 246-55. ©2017 AACR.


Subject(s)
Benzocycloheptenes/pharmacology , Carcinoma, Pancreatic Ductal/drug therapy , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazoles/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzocycloheptenes/administration & dosage , Carcinoma, Pancreatic Ductal/immunology , Cell Line, Tumor , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Humans , Male , Mice, Inbred C57BL , Mice, Transgenic , Molecular Targeted Therapy , Pancreatic Neoplasms/immunology , Triazoles/administration & dosage , Xenograft Model Antitumor Assays , Gemcitabine , Axl Receptor Tyrosine Kinase
2.
Cancer Res ; 75(18): 3699-705, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26206560

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.


Subject(s)
Carcinoma, Pancreatic Ductal/drug therapy , Epithelial-Mesenchymal Transition/drug effects , Intercellular Signaling Peptides and Proteins/physiology , Neoplasm Proteins/physiology , Pancreatic Neoplasms/drug therapy , Proto-Oncogene Proteins/physiology , Receptor Protein-Tyrosine Kinases/physiology , Warfarin/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , 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 , Female , Gene Knockdown Techniques , Humans , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Proteins/antagonists & inhibitors , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , RNA, Small Interfering/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Signal Transduction/drug effects , Specific Pathogen-Free Organisms , Warfarin/administration & dosage , Warfarin/therapeutic use , Xenograft Model Antitumor Assays , Gemcitabine , Axl Receptor Tyrosine Kinase
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