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

Kathleen F Ludwig; Wenting Du; Noah B Sorrelle; Katarzyna Wnuk-Lipinska; Mary Topalovski; Jason E Toombs; Victoria H Cruz; Shinichi Yabuuchi; N V Rajeshkumar; Anirban Maitra; James B Lorens; Rolf A Brekken

doi:10.1158/0008-5472.CAN-17-1973

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

Cancer Res. 2018 Jan 1;78(1):246-255. doi: 10.1158/0008-5472.CAN-17-1973. Epub 2017 Nov 27.

Authors

Affiliations

¹ Division of Pediatric Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
² Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
³ BerGenBio AS, Bergen, Norway.
⁴ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁵ Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁶ Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.
⁷ Hamon Center for Therapeutic Oncology Research, Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. [email protected].
⁸ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.

^# Contributed equally.

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.

Publication types

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

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Axl Receptor Tyrosine Kinase
Benzocycloheptenes / administration & dosage
Benzocycloheptenes / pharmacology*
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / immunology
Cell Line, Tumor
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives
Female
Gemcitabine
Humans
Male
Mice, Inbred C57BL
Mice, Transgenic
Molecular Targeted Therapy
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / immunology
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Triazoles / administration & dosage
Triazoles / pharmacology*
Xenograft Model Antitumor Assays

Substances

Benzocycloheptenes
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Triazoles
bemcentinib
Deoxycytidine
Receptor Protein-Tyrosine Kinases
Gemcitabine
Axl Receptor Tyrosine Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding