> Details

Welti, Jonathan; Sharp, Adam; Yuan, Wei; Dolling, David; Nava Rodrigues, Daniel; Figueiredo, Ines; Gil, Veronica; Neeb, Antje; Clarke, Matthew; Seed, George; Crespo, Mateus; Sumanasuriya, Semini; Ning, Jian; Knight, Eleanor; Francis, Jeffrey C.; Hughes, Ashley; Halsey, Wendy S.; Paschalis, Alec; Mani, Ram S.; Raj, Ganesh V.; Plymate, Stephen R.; Carreira, Suzanne; Boysen, Gunther; Chinnaiyan, Arul M.; [...]

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

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
  • Contributor: Welti, Jonathan; Sharp, Adam; Yuan, Wei; Dolling, David; Nava Rodrigues, Daniel; Figueiredo, Ines; Gil, Veronica; Neeb, Antje; Clarke, Matthew; Seed, George; Crespo, Mateus; Sumanasuriya, Semini; Ning, Jian; Knight, Eleanor; Francis, Jeffrey C.; Hughes, Ashley; Halsey, Wendy S.; Paschalis, Alec; Mani, Ram S.; Raj, Ganesh V.; Plymate, Stephen R.; Carreira, Suzanne; Boysen, Gunther; Chinnaiyan, Arul M.; [...]
  • imprint: American Association for Cancer Research (AACR), 2018
  • Published in: Clinical Cancer Research
  • Language: English
  • DOI: 10.1158/1078-0432.ccr-17-3571
  • ISSN: 1078-0432; 1557-3265
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.</jats:p> <jats:p>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 models.</jats:p> <jats:p>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 prostate cancer 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.</jats:p> <jats:p>Conclusions: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies. Clin Cancer Res; 24(13); 3149–62. ©2018 AACR.</jats:p>
  • Access State: Open Access