Abstract 5851: Identifying novel genetic mechanism underlying ADT resistance in African American patients
Authors: Ganaie Arsheed A. , Hussain Tabish , Ferrari Marina , Astone Matteo , Hoeppner Luke , Schuster Todd , Murugan Pari Murugan , Konety Badrinath R. , Saleem Mohammad 
Published: August 2018

Abstract
Enzalutamide has recently been introduced in clinics to treat castration-resistant prostate cancer (CRPC) condition, however has failed to significantly improve the overall survival in patients. Similar to bicalutamide, Enzalutamide therapy is reported not to be significantly beneficial in blocking emergence of refractory CRPC in high-risk patients such as in African-American (AA) men who exhibit (i) aggressive prostate cancer (PCa), (ii) worse survival than Caucasians (CA), and (iii) poor response to ADT. Intrinsic genetic differences play an important role in race-related PCa disparities, and there is no concrete data available explaining Enzalutamide-therapy failure in AA PCa patients. In this study, we developed genetically distinct Enzalutamide-resistance cell models representing PCa in CA and AA men, and studied their characteristics in terms of proliferation, prostatosphere formation, in vivo metastasis in a transgenic zebra-fish model and responsiveness to Enzalutamide therapy in athymic mouse model. We show that Enzalutamide-therapy increases the enrichment of cancer stem (S/P) and epithelial-mesenchymal-transition (EMT) cell populations. We provide evidence that short-term and long-term (4-months) of Enzalutamide-therapy results in the induction of AR expression in resistant-Caucasian (LNCaP95-Enz) model, whereas no effect on AR-pathway is observed in resistant AA models (RC-77T/E and E006AA-hT). Because AKT pathway has been shown to drive CRPC in ADT-resistant cases, we tested efficacy of AKT-inhibitor therapy in Enzalutamide-resistant AA and CA models. Whereas Enzalutamide-resistant CA models were responsive to AKT-inhibitor therapy, AA models exhibited non-responsiveness. To understand the exact molecular mechanism of drug-resistance induced by Enzalutamide, we hypothesized that this phenomenon could be associated to the aberration of molecules (at genetic and epigenetic levels). We performed RNA-seq analysis to study global gene expression, mircoRNA and LncRNA expression profile in Enzalutamide-responsive and Enzalutamide-resistant AA PCa models. We show that non-AR mediated genetic and epigenetic mechanisms play significant role in drug-resistance in AA PCa. We established an AA-specific molecular signature of 2 genes; 3 micro-RNA's and 1 LncRNA. The data was validated in cell models and tumor specimens (primary and METS) of CA and AA patients. We identified BAMBi as a lead biomarker that differentiates responsive-PCa e from Enzalutamide-resistant PCa in AA men, and conducted functional studies to validate its significance as a therapeutic target. To summarize, our study provides detailed information about the changes in genetic and epigenetic landscape which occur during the PCa progression and form the basis of novel race-specific biomarkers of Enzalutamide-resistance and therapeutic targets in AA PCa patients.
Citation Format: Arsheed A. Ganaie, Tabish Hussain, Marina Ferrari, Matteo Astone, Luke Hoeppner, Todd Schuster, Pari Murugan Murugan, Badrinath R. Konety, Mohammad Saleem. Identifying novel genetic mechanism underlying ADT resistance in African American patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5851.