Abstract 2328: Race specific hyper-activation of CCR9-mediated survival signals and its impact on efficacy of docetaxel in prostate cancer

Abstract

Abstract Current approaches to treat and manage prostate cancer (PCa) have failed to reduce racial disparity primarily due to undefined molecular mechanism. We have shown higher expression of chemokine receptor-9 in PCa cells and CCR9 expression was higher in PCa cells (MDA-PCa-2b) derived from African American (AA) patient compared to PCa cells derived form European American (EA) patients (LNCaP and PC3). Using antibody microarray we observed hyper activation of survival molecules and down-regulation of apoptotic molecules in AA PCa cells compared to EA PCa cell lines, following CCL25 stimulation. Comparative heat map analysis showed significant increase (~2-3 fold) in phosphorylation of pro-survival proteins in AA cells compared to EA cells treated with CCL25, which was further confirmed by western blot analysis. Furthermore, CCL25 treated PCa cells showed decreased expression of pro-apoptotic proteins (Bim, Bid, Bak), which was significantly abrogated by CCR9 shRNA. This effect was more pronounced in AA cells compared to EA cells. Efficacy of docetaxel (DTX) was higher after CCR9 blockade in presence of CCL25 compared to cells treated with CCL25 without blocking CCR9. Improvement in efficacy of DTX was due to inhibition of cell survival and activation of pro-apoptotic signals following CCR9 blockade. These observations suggest potential involvement of CCR9 mediated molecular pathways in disparity associated with outcome of PCa. Citation Format: Neeraj Kapur, Hina Mir, Guru Sonpavde, Shailesh Singh. Race specific hyper-activation of CCR9-mediated survival signals and its impact on efficacy of docetaxel in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2328. doi:10.1158/1538-7445.AM2017-2328