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Targeting Poly(ADP-Ribose) Polymerase and the c-Myb–Regulated DNA Damage Response Pathway in Castration-Resistant Prostate Cancer

Authors :
Jianhua Yin
Bradley M. Broom
Styliani Karanika
Theodoros Karantanos
Hirayama Takahiro
Guang Yang
Nora M. Navone
Jianxiang Wang
Elsa M. Li Ning Tapia
Paul G. Corn
Hyun-Sung Lee
Patricia Troncoso
Sankar N. Maity
Likun Li
Masato Dobashi
Sanghee Park
Lianchun Xiao
Ju Seog Lee
Timothy C. Thompson
Parantu K. Shah
Chengzhen Ren
Wenling Zhang
Eleni Efstathiou
Wenjun Chang
Ana Aparicio
Source :
Science Signaling. 7
Publication Year :
2014
Publisher :
American Association for the Advancement of Science (AAAS), 2014.

Abstract

Androgen deprivation is the standard treatment for advanced prostate cancer (PCa), but most patients ultimately develop resistance and tumor recurrence. We found that MYB is transcriptionally activated by androgen deprivation therapy or genetic silencing of the androgen receptor (AR). MYB silencing inhibited PCa growth in culture and xenografts in mice. Microarray data revealed that c-Myb and AR shared a subset of target genes that encode DNA damage response (DDR) proteins, suggesting that c-Myb may supplant AR as the dominant regulator of their common DDR target genes in AR inhibition-resistant or AR-negative PCa. Gene signatures including AR, MYB, and their common DDR-associated target genes positively correlated with metastasis, castration resistance, tumor recurrence, and decreased survival in PCa patients. In culture and in xenograft-bearing mice, a combination strategy involving the knockdown of MYB, BRCA1, or TOPBP1 or the abrogation of cell cycle checkpoint arrest with AZD7762, an inhibitor of the checkpoint kinase Chk1, increased the cytotoxicity of the poly[adenosine 5'-diphosphate (ADP)-ribose] polymerase (PARP) inhibitor olaparib in PCa cells. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the DDR pathway involving c-Myb, TopBP1, ataxia telangiectasia mutated- and Rad3-related (ATR), and Chk1.

Details

ISSN :
19379145 and 19450877
Volume :
7
Database :
OpenAIRE
Journal :
Science Signaling
Accession number :
edsair.doi.dedup.....9591708b9b346e877d216341d6ff237a
Full Text :
https://doi.org/10.1126/scisignal.2005070