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

被引：130

作者：

Ludwig, Kathleen F. ^{[1
,2
]}

Du, Wenting ^{[2
]}

Sorrelle, Noah B. ^{[2
]}

Wnuk-Lipinska, Katarzyna ^{[3
]}

Topalovski, Mary ^{[2
]}

Toombs, Jason E. ^{[2
]}

Cruz, Victoria H. ^{[2
]}

Yabuuchi, Shinichi ^{[4
]}

Rajeshkumar, N. V. ^{[4
,9
]}

Maitra, Anirban ^{[5
,6
]}

Lorens, James B. ^{[7
]}

Brekken, Rolf A. ^{[2
,8
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Div Pediat Oncol, Dallas, TX 75390 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Surg, Div Surg Oncol, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[3] BerGenBio AS, Bergen, Norway

[4] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[7] Univ Bergen, Norwegian Ctr Excellence, Ctr Canc Biomarkers, Dept Biomed, Bergen, Norway

[8] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[9] Intrexon Corp, Human Therapeut Div, Germantown, MD USA

来源：

CANCER RESEARCH | 2018年 / 78卷 / 01期

关键词：

TO-MESENCHYMAL TRANSITION; DRUG-RESISTANCE; DENDRITIC CELLS; KINASE; ACTIVATION; TBK1; PROMOTES; METASTASIS; SURVIVAL; CHEMORESISTANCE;

D O I：

10.1158/0008-5472.CAN-17-1973

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-NF kappa B 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. (C) 2017 AACR.

引用

页码：246 / 255

页数：10

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