Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade

Vivek K. Arora, Emily Schenkein, Rajmohan Murali, Sumit K. Subudhi, John Wongvipat, Minna D. Balbas, Neel Shah, Ling Cai, Eleni Efstathiou, Chris Logothetis, Deyou Zheng, Charles L. Sawyers

Research output: Contribution to journalArticle

404 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1309-1322
Number of pages14
JournalCell
Volume155
Issue number6
DOIs
StatePublished - Dec 5 2013

Fingerprint

Androgen Antagonists
Glucocorticoid Receptors
Androgen Receptors
Prostatic Neoplasms
Genes
Cytoplasmic and Nuclear Receptors
Pharmaceutical Preparations
Dexamethasone
Tumors
Up-Regulation
Cells
Maintenance
Phenotype
Feedback
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Arora, V. K., Schenkein, E., Murali, R., Subudhi, S. K., Wongvipat, J., Balbas, M. D., ... Sawyers, C. L. (2013). Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell, 155(6), 1309-1322. https://doi.org/10.1016/j.cell.2013.11.012

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 journalArticle

Arora, VK, Schenkein, E, Murali, R, Subudhi, SK, Wongvipat, J, Balbas, MD, Shah, N, Cai, L, Efstathiou, E, Logothetis, C, Zheng, D & Sawyers, CL 2013, 'Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade', Cell, vol. 155, no. 6, pp. 1309-1322. https://doi.org/10.1016/j.cell.2013.11.012
Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013 Dec 5;155(6):1309-1322. https://doi.org/10.1016/j.cell.2013.11.012
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. / Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. In: Cell. 2013 ; Vol. 155, No. 6. pp. 1309-1322.
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