Abstract 3189: Neuronal transcription factor BRN2 is an androgen suppressed driver of neuroendocrine differentiation in prostate cancer
Authors: Bishop Jennifer L. , Thaper Daksh , Vahid Sepideh , Munuganti Ravi S. , Ahn Paul , Davies Alastair , Ketola Kirsi , Nip Ka Mun , Lin Dong , Wang Yuzhuo , Beltran Himisha , Zoubeidi Amina 
Published: July 2017

Neuroendocrine prostate cancer (NEPC) is an incurable, rapidly progressing and lethal disease. NEPC is increasingly recognized as a highly therapy resistant tumor variant that evolves from castration-resistant prostate cancer (CRPC) in a subset of patients treated with potent androgen receptor (AR) pathway inhibitors like enzalutamide (ENZ). Importantly, mechanisms by which the AR directly controls the emergence of NEPC from CRPC under the selective pressure of ENZ remain elusive. As the AR is the cornerstone therapeutic target in men with CRPC, understanding its contribution to the development of NEPC is critical to better implement current standard-of-care therapies such as ENZ, and to identify novel therapeutic targets for this incurable disease. Hallmarks of NEPC are resistance to ENZ and the loss or reduced activity of the AR. Thus, we hypothesized that a consequence of ENZ treatment and resistance in CRPC is relief of AR-mediated suppression of factors that drive NEPC. To investigate this, we developed a model of prostate cancer that mimics clinical progression to CRPC and ENZ resistance (ENZR CPRC). Mirroring what is observed in some patients who progress on ENZ, 25% of our ENZR CRPC tumors and derived cell lines showed strong reduction in classic activity of the AR and a NEPC phenotype. By interrogating NEPC-like ENZR CRPC and ENZ-treated CRPC tumors and cell lines with RNA-Seq and mechanistic in vitro and in vivo studies, as well as human tumors with RNA-Seq and IHC, we identified the master neural transcription factor BRN2 as a central and clinically relevant driver of NEPC differentiation. Specifically, we found AR binding in the BRN2 enhancer directly represses BRN2 transcription and this release drives NEPC marker expression and aggressive growth of ENZR CRPC. Our data also reveal a striking overlap of AR and SOX binding motifs in the enhancer region of BRN2 creating a competitive binding scenario between AR and SOX2, another cell-fate determining transcription factor associated with NEPC. We discovered that upregulation of BRN2 further enhances SOX2 expression and that a BRN2-SOX2 interaction contributes to NEPC differentiation. Importantly, we found BRN2 is highly expressed in human NEPC and metastatic CRPC, especially in patients with low AR activity, highlighting its clinical relevance to disease that is difficult to treat with mainstay therapies. These data underscore the consequences of potent AR inhibition in CRPC, revealing a novel mechanism of AR-dependent control of NEPC via direct suppression of BRN2. This work uncovers BRN2 as a clinically relevant potential therapeutic target to prevent emergence of NEPC from ENZR CRPC.

Citation Format: Jennifer L. Bishop, Daksh Thaper, Sepideh Vahid, Ravi S. Munuganti, Paul Ahn, Alastair Davies, Kirsi Ketola, Ka Mun Nip, Dong Lin, Yuzhuo Wang, Himisha Beltran, Amina Zoubeidi. Neuronal transcription factor BRN2 is an androgen suppressed driver of neuroendocrine differentiation 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 3189. doi:10.1158/1538-7445.AM2017-3189