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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1309-1322 |
| Number of pages | 14 |
| Journal | Cell |
| Volume | 155 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 5 2013 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. / Arora, Vivek K.; Schenkein, Emily; Murali, Rajmohan; Subudhi, Sumit K.; Wongvipat, John; Balbas, Minna D.; Shah, Neel; Cai, Ling; Efstathiou, Eleni; Logothetis, Chris; Zheng, Deyou; Sawyers, Charles L.
In: Cell, Vol. 155, No. 6, 05.12.2013, p. 1309-1322.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade
AU - Arora, Vivek K.
AU - Schenkein, Emily
AU - Murali, Rajmohan
AU - Subudhi, Sumit K.
AU - Wongvipat, John
AU - Balbas, Minna D.
AU - Shah, Neel
AU - Cai, Ling
AU - Efstathiou, Eleni
AU - Logothetis, Chris
AU - Zheng, Deyou
AU - Sawyers, Charles L.
PY - 2013/12/5
Y1 - 2013/12/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84890078624&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890078624&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.11.012
DO - 10.1016/j.cell.2013.11.012
M3 - Article
C2 - 24315100
AN - SCOPUS:84890078624
VL - 155
SP - 1309
EP - 1322
JO - Cell
JF - Cell
SN - 0092-8674
IS - 6
ER -