Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-01, Vol.78 (1), p.246-255
• Main Authors: Ludwig, Kathleen F, Du, Wenting, Sorrelle, Noah B, Wnuk-Lipinska, Katarzyna, Topalovski, Mary, Toombs, Jason E, Cruz, Victoria H, Yabuuchi, Shinichi, Rajeshkumar, N V, Maitra, Anirban, Lorens, James B, Brekken, Rolf A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Axl protein; Benzocycloheptenes - administration & dosage; Benzocycloheptenes - pharmacology; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - immunology; Cell Line, Tumor; Chemotherapy; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Drug resistance; Enzyme inhibitors; Female; Gemcitabine; Humans; Inhibitors; Male; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; NF-κB protein; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Triazoles - administration & dosage; Triazoles - pharmacology; Tumor cells; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-1973

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 and enhance gemcitibine efficacy 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. These results establish a preclinical mechanistic rationale for the clinical development of AXL inhibitors to improve the treatment of PDAC patients. .