Combined Inhibition Of Androgen Signaling And Apoptosis Pathways In Hormone Sensitive Prostate Cancer

Abstract In the United States, where prostate cancer (PC) screening is common, over 90% of patients present initially with localized or locally advanced disease. Over the past decade, research has confirmed that PC tumor cells' response to the presence of androgen (testosterone) is a principal driver of PC. Men with PC who recur after surgery or radiation frequently undergo androgen deprivation therapy (ADT), wherein androgen exposure is chemically diminished. However, it is frequently followed by resistance, androgen-independent growth, and eventually the development of metastatic castration-resistant prostate cancer (mCRPC), the most lethal form of the disease. For those cancers that become mCRPC, many respond to other forms of ADT or chemotherapy. Therefore, it is vital to investigate additional therapeutic strategy to delay or prevent the transition of hormone sensitive cancer to mCRPC. In response to stress signals from anti-cancer therapies, malignant cells may express pro-apoptotic activator proteins, such as the expression of the Bcl2 family of proteins. The block in apoptosis (Bcl2 family) that keeps cancer cells alive in response to anti-cancer agents is therefore an attractive candidate for targeted therapies. Previous studies have documented that overexpression of Bcl2 family proteins are associated with therapeutic resistance of PC, disease recurrence and shortened survival in CRPC. However, association between androgen signaling pathways and Bcl2 family proteins is not clearly understood. In our current study we observed that treatment with androgen inhibits the expression of Bcl2 family proteins (Bcl2, Bcl-w, Bcl-xL) in hormone sensitive human PC LNCaP cell lines. Importantly, we also observed that treatment with the androgen receptor (AR) inhibitor enzalutamide restores their (Bcl2, Bcl-w, Bcl-xL) expression even when treated with a very low concentration. This data indicates that there is direct negative-regulation of the Bcl2 family of proteins by the AR-signaling pathway. We also observed that there is synergistic effect of enzalutamide and the Bcl2-inhibitor venetoclax on growth inhibition of LNCaP cells. Our current study develops a rationale for combining enzalutamide or other androgen signaling agent inhibitors with Bcl2 targeted therapies for hormone sensitive prostate cancer. We believe this combinatorial therapeutic approach will show great potential for future clinical trials of high-risk hormone sensitive PC patients and may block the ADT-induced shift of hormone sensitive PC to mCRPC. Citation Format: Goutam Chakraborty, Rahim Hirani, Lina E. Jehane, Ying Z. Mazzu, Yuki Yoshikawa, Sai Harisha Rajanala, Gwo-Shu M. Lee, Philip W. Kantoff. Combined inhibition of androgen signaling and apoptosis pathways in hormone sensitive prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6219.