Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.
Cell, 2013/12/05;155(6):1309-22.
Arora VK[1], Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, Zheng D, Sawyers CL
Affiliations
PMID: 24315100
Impact factor: 66.85
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.
MeSH terms
Androgen Antagonists; Androgen Receptor Antagonists; Animals; Benzamides; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression Regulation; Heterografts; Humans; Male; Mice; Neoplasm Transplantation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Receptors, Glucocorticoid; Transcriptome
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