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

Research output: Contribution to journalArticle

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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–NFkB 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.

Original languageEnglish (US)
Pages (from-to)246-255
Number of pages10
JournalCancer Research
Volume78
Issue number1
DOIs
StatePublished - Jan 1 2018

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Pancreatic Neoplasms
gemcitabine
Drug Therapy
Nucleoside Transport Proteins
Immune Evasion
Neoplasms
Tumor Microenvironment
Drug Resistance
Phosphotransferases
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Small-molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer. / 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.

In: Cancer Research, Vol. 78, No. 1, 01.01.2018, p. 246-255.

Research output: Contribution to journalArticle

Ludwig, KF, Du, W, Sorrelle, NB, Wnuk-Lipinska, K, Topalovski, M, Toombs, JE, Cruz, VH, Yabuuchi, S, Rajeshkumar, NV, Maitra, A, Lorens, JB & Brekken, RA 2018, 'Small-molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer', Cancer Research, vol. 78, no. 1, pp. 246-255. https://doi.org/10.1158/0008-5472.CAN-17-1973
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. / Small-molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer. In: Cancer Research. 2018 ; Vol. 78, No. 1. pp. 246-255.
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