Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)

Abstract

Welti et al; Targeting BET family proteins in CRPC 2 Statement of Translational RelevanceAdvanced prostate cancer invariably progresses to lethal castration resistant prostate cancer (CRPC). Resistance to current androgen receptor (AR) targeting therapies is associated with the development of AR aberrations including the constitutively active AR splice variant 7 (AR-V7). Currently, no clinically available therapies effectively inhibit aberrant AR signaling. BRD4, a bromodomain and extraterminal (BET) family protein, is a critical AR coregulator. We show that BRD4 expression associates with patient outcome and AR driven transcription in lethal prostate cancer. Moreover, BET inhibitors (BETi) reduce AR splicing and AR-V7 expression by regulating alternative splicing, abrogating AR signaling and inhibiting growth of CRPC patient derived models. Clinical studies with BETi in CRPC should pursue pharmacodynamics studies evaluating abrogation of AR splicing and persistent AR signaling to optimize the development of these drugs for the treatment of CRPC.Research. Experimental Design: We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models.Results: Nuclear BRD4 protein expression increases significantly (p=<0.01) with castration resistance in same patient treatment naïve (median H-score; interquartile range: 100; 100-170) and CRPC (150; 110-200) biopsies, with higher expression at diagnosis associating with worse outcome (HR 3.25, 95% CI 1.50-7.01; p=<0.001). BRD2, BRD3 and BRD4 RNA expression in CRPC biopsies correlates with AR driven transcription (all p=<0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of PC cells and patient derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (p=<0.001) of a patient derived xenograft model of CRPC with AR amplification and AR-V7 expression. Conclusion:BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof of mechanism pharmacodynamic studies.

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

“…Moreover, high BRD2 expression in primary tumors was associated with shorter PC-specific survival . More recently, the nuclear BRD4 protein level was confirmed to increase following castration resistance in longitudinally matched tumor samples collected pre and post treatment (Welti et al 2018). We also found that high expression of ATAD2 was positively associated with biochemical recurrence on a cohort of 10,000 patients .…”

LSD1: A single target to combat lineage plasticity in lethal prostate cancer

“…Transcriptional signatures from intermediate adenocarcinoma patients overlapped with datasets from neuroendocrine prostate cancer patients, suggesting that in the context of retained AR function, tumors can also activate lineage plasticity networks to evade ADT without shutting down AR expression. Evidence of this exists where enzalutamideresistant preclinical models with AR expression have shown benefit from disruption of bromo-and extraterminal domain (BET) bromodomain proteins by BET inhibitors (14,15). Overall, BET inhibitors enhanced efficacy and reversed resistance to AR antagonists.…”

The epigenetic and transcriptional landscape of neuroendocrine prostate cancer

“…Epigenetic drugs targeting the BET family of chromatin readers and transcriptional regulators, such as BRD4, are also in clinical development. Pre-clinical studies have shown that drugs targeting BRD4 disrupt its recruitment to chromatin sites bound by AR, suppress signaling, and, alone or in combination with ARPIs, demonstrate anti-tumour activity (Asangani et al 2014, Welti et al 2018. This is due, in part,to the requirement of BRD4 activity to mediate chromatin accessibility and AR transcriptional reprogramming during prostate cancer progression (Urbanucci et al 2017).…”