Abstract 1821: Identifying a novel mechanism underlying the enzalutamide and bicalutamide resistance in African-American prostate cancer patients

Abstract

Abstract Recently, FDA approved the Enzalutamide as a drug for castration-resistant prostate cancer. Recent studies reported patient populations which are non-responsive to the Enzalutamide therapy. Notably, African-American patients do not fare well for the castration-therapies (Bicalutamide and Enzalutamide). To identify a new therapeutic strategy for such populations, it is very important to understand the mechanism underlying the resistance to Bicalutamide or Enzalutamide. This would involve the use of an appropriate Bicalutamide or Enzalutamide-resistant model. We hypothesized that heterogeneous sub-populations contribute to Enzalutamide and bicalutamide resistance. In this study, we generated cell models representing Bicalutamide- and Enzalutamide-resistant phenotypes of primary prostate tumor of African-Americans. We next isolated subpopulations of Enzalutamide RC-Enz; Eht-Enz) and bicalutamide-resistant (RCbc; Eht-bc) cells. The cell sub-populations were ranked into three major classes’ viz., (1) highly stem-cell like (expressing several stemness markers BMI1 & CD133), (2) less stem-cell like (express one stemness marker BM1), and (3) non-stem cell like (negative for BMI1 and CD133). Notably, African-American primary CaP cells exhibited higher number of stem cell-like populations than Caucasian primary (22Rν1) and metastatic cells (PC3). When compared, the African-American Enzalutamide/Bicalutamide-resistant stem cell-like (RC-EnzCD133+/BM1+, RC-bcCD133+/BM1+, Eht-bcCD133+/BM1+ & Eht-EnzCD133+/BM1+) cells exhibited increased rate of proliferation, invasiveness and migration than Enzalutamide-resistant Caucasian stem cell-like cells(LNCaP95EnzCD133+/BM1+). We show that RC-EnzCD133+/BM1+ and RC-bcCD133+/BM1+ cells resistant cells exhibit increased (i) promoter activity of BMI1 gene, (ii) localization of BMI1 protein on PTEN gene, and (iii) physical interaction of BMI1 tumor to E4F1 tumor suppressor protein. This was validated in prostatic tumors of African-Americans. We provide evidence that E4F1 under normal conditions negatively regulates the activity of Androgen receptor (AR)-associated signaling and inhibits growth of cells. We show that BMI1 protein sequesters E4F1 protein and inhibits its check-point type or negative regulation of AR-pathway in Enzalutamide and Bicalutamide-resistant cells. This leads to the growth of stem-cell like tumor cells during the Enzalutamide and Bicalutamide therapies. To conclude, we suggest that (1) E4F1-regulated AR-signaling plays an important role in prostate cancer, particularly in African-Americans, (2) ratio of E4F1 and BM1 expression has the potential as a biopsy biomarker for deciding the disease phenotype and (3) E4F1/BMI1 as a therapeutic target could be exploited to increase the sensitivity to Enzalutamide and Bicalutamide therapies in African-Americans. Citation Format: Arsheed Ganaie, Badrinath R. Konety, Todd Schuster, Mohammad Saleem. Identifying a novel mechanism underlying the enzalutamide and bicalutamide resistance in African-American prostate cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1821.