Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer.
Sci Rep
; 9(1): 3823, 2019 03 07.
Article
em En
| MEDLINE
| ID: mdl-30846826
ABSTRACT
The BET bromodomain protein BRD4 is a chromatin reader that regulates transcription, including in cancer. In prostate cancer, specifically, the anti-tumor activity of BET bromodomain inhibition has been principally linked to suppression of androgen receptor (AR) function. MYC is a well-described BRD4 target gene in multiple cancer types, and prior work demonstrates that MYC plays an important role in promoting prostate cancer cell survival. Importantly, several BET bromodomain clinical trials are ongoing, including in prostate cancer. However, there is limited information about pharmacodynamic markers of response or mediators of de novo resistance. Using a panel of prostate cancer cell lines, we demonstrated that MYC suppression-rather than AR suppression-is a key determinant of BET bromodomain inhibitor sensitivity. Importantly, we determined that BRD4 was dispensable for MYC expression in the most resistant cell lines and that MYC RNAi + BET bromodomain inhibition led to additive anti-tumor activity in the most resistant cell lines. Our findings demonstrate that MYC suppression is an important pharmacodynamic marker of BET bromodomain inhibitor response and suggest that targeting MYC may be a promising therapeutic strategy to overcome de novo BET bromodomain inhibitor resistance in prostate cancer.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Prostata
Base de dados:
MEDLINE
Assunto principal:
Azepinas
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Triazóis
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Regulação Neoplásica da Expressão Gênica
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Proteínas Proto-Oncogênicas c-myc
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Resistencia a Medicamentos Antineoplásicos
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Neoplasias de Próstata Resistentes à Castração
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Antineoplásicos
Limite:
Humans
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Male
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos