Format

Send to

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

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

Author information

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. rolf.brekken@utsouthwestern.edu.
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.

PMID:
29180468
PMCID:
PMC5754222
DOI:
10.1158/0008-5472.CAN-17-1973
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center