Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC).
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Embargo End Date
Authors
Welti, J
Sharp, A
Yuan, W
Dolling, D
Nava Rodrigues, D
Figueiredo, I
Gil, V
Neeb, A
Clarke, M
Seed, G
Crespo, M
Sumanasuriya, S
Ning, J
Knight, E
Francis, JC
Hughes, A
Halsey, WS
Paschalis, A
Mani, RS
Raj, GV
Plymate, SR
Carreira, S
Boysen, G
Chinnaiyan, AM
Swain, A
de Bono, JS
International SU2C/PCF Prostate Cancer Dream Team,
Sharp, A
Yuan, W
Dolling, D
Nava Rodrigues, D
Figueiredo, I
Gil, V
Neeb, A
Clarke, M
Seed, G
Crespo, M
Sumanasuriya, S
Ning, J
Knight, E
Francis, JC
Hughes, A
Halsey, WS
Paschalis, A
Mani, RS
Raj, GV
Plymate, SR
Carreira, S
Boysen, G
Chinnaiyan, AM
Swain, A
de Bono, JS
International SU2C/PCF Prostate Cancer Dream Team,
Document Type
Journal Article
Date
2018-07-01
Date Accepted
2018-03-14
Abstract
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.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.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.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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (13), pp. 3149 - 3162
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Development & Cancer
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Development & Cancer