Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.
Cell
; 155(6): 1309-22, 2013 Dec 05.
Article
em En
| MEDLINE
| ID: mdl-24315100
ABSTRACT
The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Feniltioidantoína
/
Neoplasias da Próstata
/
Receptores de Glucocorticoides
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Resistencia a Medicamentos Antineoplásicos
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Antagonistas de Receptores de Andrógenos
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Antagonistas de Androgênios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
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Male
Idioma:
En
Revista:
Cell
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos