Abstract
Abstract Development of chemo-resistance negatively impacts therapeutic outcome of advanced prostate cancer (PCa). Molecular mechanism used by cancer cells to overcome therapeutic effect is still undefined. Here, we demonstrate the influence of CXCR6/CXCL16 mediated molecular signals on the efficacy of docetaxel (DTX). Out data showed poor DTX efficacy on PCa cells (LNCaP, PC3, and DU145) after stimulating CXCR6 with soluble CXCL16, while significant improvement in cytotoxic effect of DTX was observed after CXCR6 blockade using anti-CXCR6 monoclonal antibody. Interestingly, CXCR6, CXCL16, and ADAM-10, a metalloproteinase involved in CXCL16 cleavage from PCa cell membranes, were significantly elevated in response to DTX treatment. This was further confirmed on xenograft tumor by immunohistochemistry. Further, phospho-proteomic profiling and western blot analysis showed activation of pro-survival molecules: GSK-3β, NFκB, ERK/1/2, and survivin following soluble CXCL16 treatment. Activation of CXCR6-CXCL16 axis also inhibited expression of the epithelial marker (E-cadherin) while increased expression of mesenchymal markers (β-catenin, α-SMA, vimentin, snail), which highlights the role of CXCR6 in promoting mesenchymal phenotype that is known to have a significant impact on cancer progression and therapeutic outcome. Thus, our study shows that CXCR6-CXCL16 signaling instigates chemotherapeutic resistance by increasing pro-survival signaling and promoting mesenchymal phenotype. Hence, combining CXCR6 blockade with DTX would be a better treatment option for advanced, drug-resistant PCa. Citation Format: Neeraj Kapur, Hina Mir, Guru Sonpavde, James W. Lillard, Shailesh Singh. CXCR6-directed therapeutic approach potentiates efficacy of docetaxel in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4803.
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