Abstract 4395: The cMYC-associated transcription factor JPO2 is upregulated in taxane resistant prostate cancer cells and interacts with the stress oncoprotein LEDGF/p75

Prostate Cancer (PCa) progression leads to an advanced stage called metastatic castration PCa (mCRPC), for which currently there is no cure in spite of advances in treatment with new generation androgen deprivation drugs and chemotherapy with taxanes such as docetaxel (DTX). Our group demonstrated previously that the stress oncoprotein Lens Epithelium Derived Growth Factor of 75 kD (LEDGF/p75) is upregulated in clinical prostate tumors and contributes to DTX-resistance in mCRPC cells. However, little is known about the molecular mechanisms by which LEDGF/p75 promotes taxane resistance. The C-terminus of LEDGF/p75 contains a domain called the Integrase Binding Domain (IBD), which in T cells is responsible for tethering the HIV-integrase complex to transcriptionally active chromatin. In cancer cells, the LEDGF/p75 IBD interacts with oncogenic transcription complexes, such as Menin-MLL and the cMYC binding protein JPO2, to promote cell survival. However, the relevance of these protein-protein interactions (PPIs) in PCa and chemoresistance has never been explored. This study is designed to characterize the interaction between LEDGF/p75 and JPO2 in the DTX-resistant mCRPC cell lines PC3-DR and DU145-DR, and determine if this interaction contributes to drug resistance. Also, we want to target this interaction with repurposed HIV-based small molecule inhibitors (SMI’s) of LEDGF/p75, which target the IBD, to abrogate this resistance. We demonstrated by immunoblotting a significant 2-fold co-upregulation of JPO2 and LEDGF/p75 in the DTX-resistant PCa cells. We also observed the nuclear co-localization of these proteins by immunofluorescence microscopy. Using an immunoprecipitation approach, we confirmed that endogenous JPO2 and LEDGF/p75 co-immunoprecipitate in the DTX-resistant PCa cells. In addition, we initiated studies to evaluate SMIs originally designed to target the interaction between LEDGF/p75 and HIV-IN, for their efficacy in sensitizing resistant cells to DTX. After screening over 100 candidate inhibitors, we selected a set of SMIs which demonstrated a 20-30% decrease in viability in DTX-resistant cells when used alone, and 40-60% when used in combination with DTX. Studies are in progress to determine if these SMIs bind to LEDGF/p75 and inhibit its interaction with JPO2 and other oncoproteins. We predict that targeting LEDGF/p75 PPIs with HVI-based SMIs will disrupt transcriptional activity contributing to DTX resistance. Our goals are to establish the contribution of PPIs to LEDGF/p75-mediated transactivation of stress oncoproteins, and target these interactions to overcome PCa chemoresistance. Citation Format: Greisha L. Ortiz Hernandez, Shannalee Martinez, Evelyn Sanchez-Hernandez, Leslimar Rios-Colon, Christina Cajigas-DuRoss, Tino Sanchez, Nouri Neamati, Carlos A. Casiano. The cMYC-associated transcription factor JPO2 is upregulated in taxane resistant prostate cancer cells and interacts with the stress oncoprotein LEDGF/p75 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4395.