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

共 29 条

[1] Overcoming mutation-based resistance to antiandrogens with rational drug design [J].

Balbas, Minna D. ;

Evans, Michael J. ;

Hosfield, David J. ;

Wongvipat, John ;

Arora, Vivek K. ;

Watson, Philip A. ;

Chen, Yu ;

Greene, Geoffrey L. ;

Shen, Yang ;

Sawyers, Charles L. .

ELIFE, 2013, 2

[2] Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation [J].

Chapman, Paul B. ;

Hauschild, Axel ;

Robert, Caroline ;

Haanen, John B. ;

Ascierto, Paolo ;

Larkin, James ;

Dummer, Reinhard ;

Garbe, Claus ;

Testori, Alessandro ;

Maio, Michele ;

Hogg, David ;

Lorigan, Paul ;

Lebbe, Celeste ;

Jouary, Thomas ;

Schadendorf, Dirk ;

Ribas, Antoni ;

O'Day, Steven J. ;

Sosman, Jeffrey A. ;

Kirkwood, John M. ;

Eggermont, Alexander M. M. ;

Dreno, Brigitte ;

Nolop, Keith ;

Li, Jiang ;

Nelson, Betty ;

Hou, Jeannie ;

Lee, Richard J. ;

Flaherty, Keith T. ;

McArthur, Grant A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (26) :2507-2516

[3] Molecular determinants of resistance to antiandrogen therapy [J].

Chen, CD ;

Welsbie, DS ;

Tran, C ;

Baek, SH ;

Chen, R ;

Vessella, R ;

Rosenfeld, MG ;

Sawyers, CL .

NATURE MEDICINE, 2004, 10 (01) :33-39

[4] ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment [J].

Clegg, Nicola J. ;

Wongvipat, John ;

Joseph, James D. ;

Tran, Chris ;

Ouk, Samedy ;

Dilhas, Anna ;

Chen, Yu ;

Grillot, Kate ;

Bischoff, Eric D. ;

Cal, Ling ;

Aparicio, Anna ;

Dorow, Steven ;

Arora, Vivek ;

Shao, Gang ;

Qian, Jing ;

Zhao, Hong ;

Yang, Guangbin ;

Cao, Chunyan ;

Sensintaffar, John ;

Wasielewska, Teresa ;

Herbert, Mark R. ;

Bonnefous, Celine ;

Darimont, Beatrice ;

Scher, Howard I. ;

Smith-Jones, Peter ;

Klang, Mark ;

Smith, Nicholas D. ;

De Stanchina, Elisa ;

Wu, Nian ;

Ouerfelli, Ouathek ;

Rix, Peter J. ;

Heyman, Richard A. ;

Jung, Michael E. ;

Sawyers, Charles L. ;

Hager, Jeffrey H. .

CANCER RESEARCH, 2012, 72 (06) :1494-1503

[5] ASSOCIATION OF GLUCOCORTICOID RECEPTORS WITH PROSTATE NUCLEAR SITES FOR ANDROGEN RECEPTORS AND WITH ANDROGEN RESPONSE ELEMENTS [J].

DAVIES, P ;

RUSHMERE, NK .

JOURNAL OF MOLECULAR ENDOCRINOLOGY, 1990, 5 (02) :117-127

[6] Abiraterone and Increased Survival in Metastatic Prostate Cancer [J].

De Bono, Johann S. ;

Logothetis, Christopher J. ;

Molina, Arturo ;

Fizazi, Karim ;

North, Scott ;

Chu, Luis ;

Chi, Kim N. ;

Jones, Robert J. ;

Goodman, Oscar B., Jr. ;

Saad, Fred ;

Staffurth, John N. ;

Mainwaring, Paul ;

Harland, Stephen ;

Flaig, Thomas W. ;

Hutson, Thomas E. ;

Cheng, Tina ;

Patterson, Helen ;

Hainsworth, John D. ;

Ryan, Charles J. ;

Sternberg, Cora N. ;

Ellard, Susan L. ;

Flechon, Aude ;

Saleh, Mansoor ;

Scholz, Mark ;

Efstathiou, Eleni ;

Zivi, Andrea ;

Bianchini, Diletta ;

Loriot, Yohann ;

Chieffo, Nicole ;

Thian Kheoh ;

Haqq, Christopher M. ;

Scher, Howard I. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (21) :1995-2005

[7] Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors [J].

Demetri, GD ;

von Mehren, M ;

Blanke, CD ;

Van den Abbeele, AD ;

Eisenberg, B ;

Roberts, PJ ;

Heinrich, MC ;

Tuveson, DA ;

Singer, S ;

Janicek, M ;

Fletcher, JA ;

Silverman, SG ;

Silberman, SL ;

Capdeville, R ;

Kiese, B ;

Peng, B ;

Dimitrijevic, S ;

Druker, BJ ;

Corless, C ;

Fletcher, CDM ;

Joensuu, H .

NEW ENGLAND JOURNAL OF MEDICINE, 2002, 347 (07) :472-480

[8] Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone [J].

Efstathiou, Eleni ;

Titus, Mark ;

Tsavachidou, Dimitra ;

Tzelepi, Vassiliki ;

Wen, Sijin ;

Anh Hoang ;

Molina, Arturo ;

Chieffo, Nicole ;

Smith, Lisa A. ;

Karlou, Maria ;

Troncoso, Patricia ;

Logothetis, Christopher J. .

JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (06) :637-643

[9] MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling [J].

Engelman, Jeffrey A. ;

Zejnullahu, Kreshnik ;

Mitsudomi, Tetsuya ;

Song, Youngchul ;

Hyland, Courtney ;

Park, Joon Oh ;

Lindeman, Neal ;

Gale, Christopher-Michael ;

Zhao, Xiaojun ;

Christensen, James ;

Kosaka, Takayuki ;

Holmes, Alison J. ;

Rogers, Andrew M. ;

Cappuzzo, Federico ;

Mok, Tony ;

Lee, Charles ;

Johnson, Bruce E. ;

Cantley, Lewis C. ;

Janne, Pasi A. .

SCIENCE, 2007, 316 (5827) :1039-1043

[10] Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and Metabolic Benefits in Patients with Cushing's Syndrome [J].

Fleseriu, Maria ;

Biller, Beverly M. K. ;

Findling, James W. ;

Molitch, Mark E. ;

Schteingart, David E. ;

Gross, Coleman .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2012, 97 (06) :2039-2049

← 1 2 3 →