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Published on: January 17, 2025
Small-Molecule Inhibition of Axl Targets Tumor Immune Suppression and Enhances Chemotherapy in Pancreatic Cancer
Kathleen F Ludwig1,2, Wenting Du2, Noah B Sorrelle2
1Division of Pediatric Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
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.
Insights
Targeting Axl kinase with BGB324 inhibits pancreatic cancer progression by improving immune response and drug sensitivity. This approach offers a new strategy to enhance treatment outcomes for pancreatic ductal adenocarcinoma (PDAC) patients.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Activation of Axl receptor tyrosine kinase correlates with poor prognosis in pancreatic cancer.
- Axl signaling contributes to immune evasion and drug resistance in pancreatic ductal adenocarcinoma (PDAC).
Purpose of the Study:
- To investigate the therapeutic potential of the selective Axl kinase inhibitor BGB324 in pancreatic cancer.
- To elucidate the mechanisms by which BGB324 affects PDAC cells and the tumor microenvironment.
Main Methods:
- In vitro studies on PDAC cells treated with BGB324.
- In vivo studies assessing gemcitabine efficacy in combination with BGB324.
- Analysis of Axl signaling pathways, including TBK1-NFκB, and immune cell modulation.
Main Results:
- BGB324 treatment promoted epithelial differentiation and nucleoside transporter expression in PDAC cells.
- The inhibitor enhanced gemcitabine efficacy in vivo.
- BGB324 modulated the tumor microenvironment, shifting it towards an immune-stimulatory state and reducing innate immune suppression.
Conclusions:
- Targeting Axl with BGB324 demonstrates preclinical efficacy against pancreatic cancer.
- Axl inhibition represents a promising strategy to overcome immune evasion and drug resistance in PDAC.
- These findings support the clinical development of Axl inhibitors for improving PDAC patient treatment.
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