Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade

被引：780

作者：

Arora, Vivek K. ^{[1
,2
]}

Schenkein, Emily ^{[1
]}

Murali, Rajmohan ^{[1
,3
]}

Subudhi, Sumit K. ^{[2
]}

Wongvipat, John ^{[1
]}

Balbas, Minna D. ^{[1
,4
]}

Shah, Neel ^{[1
,4
]}

Cai, Ling ^{[1
]}

Efstathiou, Eleni ^{[5
]}

Logothetis, Chris ^{[5
]}

Zheng, Deyou ^{[6
,7
]}

Sawyers, Charles L. ^{[1
,8
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY 10065 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA

[6] Albert Einstein Coll Med, Dept Neurol, Dept Genet, Bronx, NY 10461 USA

[7] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA

[8] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

CELL | 2013年 / 155卷 / 06期

关键词：

PROSTATE-CANCER; INCREASED SURVIVAL; LUNG-CANCER; ABIRATERONE; ENZALUTAMIDE; INHIBITION; GEFITINIB; MUTATION; GROWTH;

D O I：

10.1016/j.cell.2013.11.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1309 / 1322

页数：14

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