TY - JOUR
T1 - Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer
AU - Li, Likun
AU - Chang, Wenjun
AU - Yang, Guang
AU - Ren, Chengzhen
AU - Park, Sanghee
AU - Karantanos, Theodoros
AU - Karanika, Styliani
AU - Wang, Jianxiang
AU - Yin, Jianhua
AU - Shah, Parantu K.
AU - Takahiro, Hirayama
AU - Dobashi, Masato
AU - Zhang, Wenling
AU - Efstathiou, Eleni
AU - Maity, Sankar N.
AU - Aparicio, Ana M.
AU - Li Ning Tapia, Elsa M.
AU - Troncoso, Patricia
AU - Broom, Bradley
AU - Xiao, Lianchun
AU - Lee, Hyun Sung
AU - Lee, Ju Seog
AU - Corn, Paul G.
AU - Navone, Nora
AU - Thompson, Timothy C.
PY - 2014/5/20
Y1 - 2014/5/20
N2 - 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 inxenograft-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 newmechanism-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.
AB - 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 inxenograft-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 newmechanism-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.
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U2 - 10.1126/scisignal.2005070
DO - 10.1126/scisignal.2005070
M3 - Article
C2 - 24847116
AN - SCOPUS:84901244617
SN - 1945-0877
VL - 7
JO - Science signaling
JF - Science signaling
IS - 326
M1 - ra47
ER -