Abstract 2055: Therapeutic resistance to BET bromodomain inhibition in prostate cancer

Prostate cancer is the most common cancer among men and a leading cause of cancer-related death in North America. Current therapies include radical prostatectomy and radiotherapy for localized disease, and androgen deprivation therapy (i.e. surgical or medical castration) for metastatic disease. Recently, we described the use of inhibitors of bromodomain and extraterminal (BET) proteins for the treatment of castration-resistant prostate cancer (CRPC), which have since undergone investigation in clinical trials. In anticipation of patients refractory to treatment with BET inhibitors, we explored the development of resistance to a clinical-grade BET inhibitor in four cell line models—VCaP, LNCaP, LNCaP-AR, and 22Rv1—by serially passaging cells in increasing concentrations of drug with matched controls in DMSO. All resistance models displayed several-fold increased IC50 values relative to control in in vitro cell viability assays. Additionally, we have modeled resistance to BET inhibition in vivo by serially passaging cell line- and patient-derived xenografts in animals treated with BET inhibition. Interrogating these models through traditional molecular techniques and next-generation sequencing, we discovered several putative mechanisms of resistance to BET inhibition that we are currently validating in our laboratory. Note: This abstract was not presented at the meeting. Citation Format: Carl G. Engelke, Rohit Malik, Steven Kregel, Irfan A. Asangani, Kari Wilder-Romans, Xia Jiang, Xuhong Cao, Corey Speers, Arul M. Chinnaiyan. Therapeutic resistance to BET bromodomain inhibition in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2055. doi:10.1158/1538-7445.AM2017-2055