@article{9fdc29ee9e8342bf868c9c7bdb19cb3f,
title = "XGlucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade",
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.",
author = "Arora, \{Vivek K.\} and Emily Schenkein and Rajmohan Murali and Subudhi, \{Sumit K.\} and John Wongvipat and Balbas, \{Minna D.\} and Neel Shah and Ling Cai and Eleni Efstathiou and Chris Logothetis and Deyou Zheng and Sawyers, \{Charles L.\}",
note = "Funding Information: We thank Phil Iaquinta, Brett Carver, Yu Chen, Phil Watson, Haley Hieronymus, Bea Darimont, and Howard Scher for helpful discussions. We thank Tom Scanlan (Portland, Oregon) for generously providing compound 15, Yu Chen for generously providing the pMItDT-EGFP vector, Agnes Viales and Liping Sun of the MSKCC Genomics Core Facility for ChIP-seq library prep and sequencing, Jeffrey Zhao for assistance with microarray data analysis, Ouathek Ouerfelli of the MSKCC organic synthesis core for synthesizing ORG34517, HuiYong Zhao and Philicia Moonsamy for technical assistance with xenograft experiments, Marina Asher of the MSKCC Pathology Core Facility for assistance with IHC, and Anuradha Gopalan for providing the tissue microarray of primary untreated prostate cancer. The work is funded by CDMRP Physician Research Training Award PC102106, NIH R01CA155169, NIH P50CA09262, U01 CA141502, and the Howard Hughes Medical Institute. The human tissue acquisition study at MDACC was given financial support from Medivation. V.K.A. is funded by a Young Investigator Award from the Prostate Cancer Foundation. C.L.S. and J.W. are coinventors of enzalutamide and ARN-509 and may be entitled to royalties. ",
year = "2013",
month = dec,
day = "5",
doi = "10.1016/j.cell.2013.11.012",
language = "English",
volume = "155",
pages = "X1309--1322",
journal = "Cell",
issn = "0092-8674",
number = "6",
}