Journal
CELL
Volume 155, Issue 6, Pages 1309-1322Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.11.012
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Funding
- CDMRP Physician Research Training Award [PC102106]
- NIH [R01CA155169, P50CA09262, U01 CA141502]
- Howard Hughes Medical Institute
- Medivation
- Prostate Cancer Foundation
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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.
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