Abstract 775: Targeting the stress survival oncoprotein LEDGF/p75 to overcome prostate cancer resistance to taxane therapy

Abstract

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in the U.S. It presents a significant health burden among African American men, who tend to develop more aggressive, chemoresistant tumors and experience higher mortality rates compared to men from other ethnic groups. Eliminating these mortality disparities will require innovative therapies for the chemoresistant form of the disease. Our group has shown previously that the stress survival protein lens epithelium-derived growth factor p75 (LEDGF/p75) is overexpressed in PCa cells and clinical tumors, and promotes resistance to the taxane drug docetaxel (DTX). This study was designed to evaluate the hypothesis that LEDGF/p75 overexpression promotes taxane chemoresistance in PCa by antagonizing drug-induced caspase-independent cell death, and that targeting this protein with small inhibitory RNAs (siRNAs) or small molecule inhibitors will restore tumor cell sensitivity. We observed that acquisition of DTX-resistance in metastatic PCa cell lines (PC3 and DU145) is associated with increased expression of LEDGF/p75. Exposure of these cell lines to increasing concentrations of the taxanes DTX, paclitaxel (PTX), and cabazitaxel (CTX), and to the non-taxane drug TRAIL for up to 72 hours revealed that DTX-resistant cells also displayed increased resistance to PTX and CTX, compared to sensitive cells, but not to TRAIL. This was assessed by viability and clonogenic assays, and microscopic examination. To determine if this resistance was associated with overexpression of LEDGF/p75, we knocked down the protein with siRNAs. This knockdown attenuated resistance to the taxanes, but had no effects on TRAIL-induced cell death. We then explored if LEDGF/p75-induced taxane resistance was associated with preservation of the structural integrity of this protein. Immunoblotting analysis revealed that LEDGF/p75 was cleaved into distinct fragments by caspases during TRAIL-induced apoptosis, leading to its inactivation. However, LEDGF/p75 remained intact during treatment with taxanes, suggesting that these drugs do not induce caspase-mediated cleavage and inactivation of this protein. To determine if LEDGF/p75 is a druggable target for overcoming taxane chemoresistance in PCa cells, we repositioned a panel of small molecule inhibitors originally designed to inhibit the interaction of the C-terminal region of this protein with HIV-1 integrase. Screening of 130 inhibitors for their cytotoxic properties in DTX-resistant and sensitive prostate cancer cells, we identified a number of inhibitors that induced cell death directly, or when combined with DTX, re-sensitized the resistant cells to the drug. These promising results provide novel insights into mechanisms by which LEDGF/p75 promotes chemoresistance in PCa cells, and have implications for the development of innovative strategies to overcome this resistance. Citation Format: Leslimar Rios Colon, Catherine Elix, Anamika Basu, Tino W. Sanchez, Nouri Neamati, Carlos A. Casiano. Targeting the stress survival oncoprotein LEDGF/p75 to overcome prostate cancer resistance to taxane therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 775. doi:10.1158/1538-7445.AM2014-775