Abstract 5411: Repositioning HIV-based small molecule inhibitors of the stress survival oncoprotein LEDGF/p75 to overcome taxane resistance in prostate cancer

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men and the leading cause of cancer-related deaths in elderly males. Although early stage PCa is treatable, many patients eventually develop castration-resistant disease (mCRPC), characterized by metastasis and resistance to therapy. Furthermore, PCa also presents a major health disparity problem as evidenced by its disproportionately high incidence and mortality in African American men compared to other racial/ethnic groups. Reducing or eliminating these disparities in PCa mortality will require innovative therapeutic approaches to circumvent chemoresistance and increase patient survival. We have previously demonstrated that lens epithelium-derived growth factor of 75 kD (LEDGF/p75) is a stress survival protein that is overexpressed in PCa cells and clinical tumors, and promotes resistance to Docetaxel (DTX), the gold standard for mCRPC chemotherapy. LEDGF/p75 has also been extensively studied as a target to inhibit HIV-1 integration into host chromatin because of its role as a key cellular cofactor of HIV integrase (IN). A series of novel and potent small molecule inhibitors (SMI) of LEDGF/p75 were previously evaluated for their potential to disrupt its interaction with HIV-IN. We hypothesized that repositioning these SMI to target LEDGF/p75 in the context of PCa could be a promising strategy for overcoming taxane resistance. We observed that PC3 and DU145 mCRPC cells selected for DTX resistance expressed high levels of LEDGF/p75, and were also resistant to the taxanes Cabazitaxel (CTX) and Paclitaxel (PTX). This chemoresistance was selective since LEDGF/p75 did not protect cells against the classical apoptotic inducer TRAIL, which triggers caspase-mediated cleavage and inactivation of LEDGF/p75. RNAi-mediated knockdown of LEDGF/p75 in these cell lines sensitized them to taxane therapy. We then evaluated 130 LEDGF/p75 SMI for their cytotoxicity in DTX-resistant and sensitive PC3 and DU145 cells, in the presence and absence of DTX. These experiments yielded a number of inhibitors that induced cell death directly or re-sensitized resistant cells to taxanes only when combined with these drugs. Our results suggest that LEDGF/p75 is a druggable oncoprotein that could be targeted with repositioned HIV-based SMI to overcome PCa chemoresistance. Citation Format: Leslimar Rios Colon, Catherine Elix, Ivana Alicea, Anamika Basu, Christina Du Ross, Tino Sanchez, Nouri Neamati, Carlos Casiano. Repo