Abstract 4700: BET bromodomain inhibition is a promising treatment strategy for distinct subsets of lethal castration-resistant prostate cancer
Authors: Gao Lina , Coleman Daniel J. , King Carly J. , Schwartzman Jacob , Wang Nicholas , Esch Amanda , Urrutia Joshua , Sehrawat Archana , Heiser Laura M. , Alumkal Joshi J. 
Published: July 2016

Background: While treatment options for patients with castration-resistant prostate cancer (CRPC) are expanding, one American man is still predicted to die every 19 minutes from this disease this year. Moreover, more widespread use of novel and more potent AR-targeting agents has led to increased clinical frequency of virulent androgen and AR-independent CRPC subsets(Small, Huang et al. 2015). Currently, there are limited treatment options for men with CRPC who are resistant to these AR-targeting agents, clearly demonstrating an urgent need to develop more effective therapies for CRPC patients.

Recent published reports demonstrate an important role for BET bromodomain chromatin reader proteins in prostate cancer models that are androgen or AR-dependent (Gao, Schwartzman et al. 2013; Wyce, Degenhardt et al. 2013; Asangani, Dommeti et al. 2014; Chan, Selth et al. 2015). However, there was limited information about the anti-tumor activity of this class of drugs in androgen-independent, enzalutamide-resistant, or AR-independent CRPC models. The studies reported herein were designed to address that deficit.

Methods: We treated a panel of CRPC cell lines with dose escalation of the BET bromodomain inhibitor JQ1 and measured cell viability. To clarify molecular mechanisms that contribute to the anti-tumor effect, we treated CRPC cell lines with JQ1 and measured gene expression changes with RNA-sequencing. Finally, to determine the anti-tumor activity of JQ1 in vivo, we implanted enzalutamide resistant or AR-null CRPC xenografts in immunocompromised mice and treated them with JQ1.

Results: All cell lines were sensitive to JQ1 with similar GI50 values (all &lt; 1μM). Our analysis of RNA-seq data after JQ1 treatment identified a BET bromodomain response signature that was conserved across the population of cell lines. Further, we applied Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis to identify novel Master Regulator transcription factors that mediate response to JQ1(Aytes, Mitrofanova et al. 2014). Finally, JQ1 treatment of enzalutamide resistant or AR-null CRPC xenografts implanted in vivo suppressed tumor growth without appreciable toxicity.

Conclusions: BET bromodomain inhibition is a promising treatment strategy for distinct subsets of lethal CRPC. Our work using a broad panel of CRPC models sheds further light on pharmacodynamic markers of response and target proteins whose function is impacted by BET bromodomain inhibition. These findings may have implications for the design of BET bromodomain inhibitor clinical trials in men with CRPC and interpretation of on-target effects in those trials.

Citation Format: Lina Gao, Daniel J. Coleman, Carly J. King, Jacob Schwartzman, Nicholas Wang, Amanda Esch, Joshua Urrutia, Archana Sehrawat, Laura M. Heiser, Joshi J. Alumkal. BET bromodomain inhibition is a promising treatment strategy for distinct subsets of lethal castration-resistant prostate cancer. [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 4700.