Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC).
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Date
2018-07-01ICR Author
Author
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,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
International SU2C/PCF Prostate Cancer Dream Team
Cell Line, Tumor
Humans
Proteins
Cell Cycle Proteins
Nuclear Proteins
Protein Isoforms
Receptors, Androgen
Transcription Factors
RNA, Small Interfering
Antineoplastic Agents
Prognosis
Treatment Outcome
Gene Expression Profiling
Computational Biology
Signal Transduction
Gene Expression Regulation, Neoplastic
Alternative Splicing
Male
Gene Knockdown Techniques
Molecular Targeted Therapy
Prostatic Neoplasms, Castration-Resistant
Biomarkers, Tumor
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Development & Cancer
Language
eng
Date accepted
2018-03-14
License start date
2018-07
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (13), pp. 3149 - 3162
Publisher
AMER ASSOC CANCER RESEARCH
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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