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

442 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade'. Together they form a unique fingerprint.

  • Cite this

    Arora, V. K., Schenkein, E., Murali, R., Subudhi, S. K., Wongvipat, J., Balbas, M. D., Shah, N., Cai, L., Efstathiou, E., Logothetis, C., Zheng, 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