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

Publication Date:
2018-07-03
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
_version_ 1836398995258212352
autor 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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
beschreibung 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_standardnr 6297196
datenlieferant ipn_articles
feed_id 9363
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-07-03
journaleissn 1557-3265
journalissn 1078-0432
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Clinical Cancer Research
relation http://clincancerres.aacrjournals.org/cgi/content/short/24/13/3149?rss=1
search_space articles
shingle_author_1 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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
shingle_author_2 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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
shingle_author_3 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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
shingle_author_4 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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
shingle_catch_all_1 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
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 .
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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_2 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
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 .
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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_3 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
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 .
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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_4 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
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 .
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, J. C., Hughes, A., Halsey, W. S., Paschalis, A., Mani, R. S., Raj, G. V., Plymate, S. R., Carreira, S., Boysen, G., International SU2; C/PCF Prostate Cancer Dream Team, Chinnaiyan, A. M., Swain, A., de Bono, J. S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_title_1 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
shingle_title_2 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
shingle_title_3 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
shingle_title_4 Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
timestamp 2025-06-30T23:35:56.101Z
titel Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
titel_suche Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC)
topic WW-YZ
uid ipn_articles_6297196