Abstract B06: Repositioning HIV-based small molecule inhibitors of the stress oncoprotein LEDGF/p75 to overcome prostate cancer resistance to taxane chemotherapy

Abstract

Abstract Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer-related deaths in men. In addition, African American (AA) men have a higher incidence of PCa with more aggressive tumors and increased mortality compared to other ethnic groups. The rise in the U.S. aging male population and the health disparities associated with this cancer type, are expected to make PCa a formidable public health and fiscal challenge in the next few decades. PCa mortality is driven by the ability of advanced prostate tumors to metastasize to vital organs and develop resistance against established anti-androgen therapies and chemotherapeutic drugs. Despite recent developments in the treatment of advanced PCa, the high mortality and the racial disparities associated with this disease still persist. For this reason, there is still an urgent medical need for innovative therapeutic approaches to reduce the burden of PCa mortality and its associated disparities. Our laboratory is at the forefront of research on the contribution of the lens epithelium-derived growth factor of 75 kD (LEDGF/p75) to PCa cancer aggressiveness. This protein is a stress response transcription coactivator that is overexpressed in PCa cells and clinical tumors, transcriptionally upregulates stress survival proteins in cancer cells, and promotes resistance to Docetaxel (DTX), the first line chemotherapeutic drug used to treat advanced PCa. Interestingly, LEDGF/p75 also plays a critical role in facilitating the integration of human immunodeficiency virus 1 (HIV-1) into active host chromatin by interacting with the HIV-integrase (HIV-IN). This biological function has made LEDGF/p75 an attractive druggable target, and for this purpose a series of novel and potent small molecule inhibitors (SMI) have been designed and studied to disrupt the interaction between HIV-IN and the C-terminal region of LEDGF/p75, which we previously implicated in its pro-survival activity. We hypothesize that repositioning these SMI for PCa treatment in combination with DTX is an innovative approach to re-sensitize DTX resistant PCa cells to chemotherapy. We observed that PC3 and DU145 cells selected for DTX resistance expressed high levels of LEDGF/p75, and were also selectively resistant to the taxanes Cabazitaxel (CTX) and Paclitaxel (PTX), but not to the classical apoptosis inducer TRAIL. Immunoblotting analysis indicated that LEDGF/p75 is cleaved and inactivated by caspases during TRAIL-induced cell death, whereas the protein remained intact in taxane treated cells. RNA interference-mediated knockdown of LEDGF/p75 in DTX-resistant cell lines sensitized them to taxane therapy. This provided proof of principle that functional inactivation of LEDGF/p75 could restore chemosensitivity. We then screened a panel of over 100 HIV-based candidate LEDGF/p75 SMI for their cytotoxicity against DTX-resistant and -sensitive PCa cells, in the presence and absence of DTX. These experiments yielded a number of inhibitors that re-sensitized the resistant cells to taxane treatment. We are currently expanding these studies to a panel of racially diverse PCa cell lines to determine the efficacy of this approach in multiple PCa cell types. Taken together, our results suggest that LEDGF/p75 is a druggable target that could potentially be functionally inactivated by repositioned HIV-based inhibitors in combination with established chemotherapeutic regimens to circumvent PCa chemoresistance and reduce the mortality disparities associated with the aggressive form of this disease. Citation Format: Leslimar Rios-Colon, Tino Wilson Sanchez, Catherine C. Elix, Ivana Alicea, Anamika Basu, Christina Du Ross, Nouri Neamati, Carlos A. Casiano. Repositioning HIV-based small molecule inhibitors of the stress oncoprotein LEDGF/p75 to overcome prostate cancer resistance to taxane chemotherapy. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B06.