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Cell. 2013 Dec 5;155(6):1309-22. doi: 10.1016/j.cell.2013.11.012.

Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

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.

PMID:
24315100
PMCID:
PMC3932525
DOI:
10.1016/j.cell.2013.11.012
[Indexed for MEDLINE]
Free PMC Article

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