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Targeting Poly(ADP-Ribose) Polymerase and the c-Myb–Regulated DNA Damage Response Pathway in Castration-Resistant Prostate Cancer
- 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.
- Subjects :
- Male
animal structures
Cell cycle checkpoint
Poly ADP ribose polymerase
Mice, Nude
Thiophenes
Poly(ADP-ribose) Polymerase Inhibitors
Biology
urologic and male genital diseases
Biochemistry
Poly (ADP-Ribose) Polymerase Inhibitor
Piperazines
Article
Olaparib
Androgen deprivation therapy
Mice
Proto-Oncogene Proteins c-myb
chemistry.chemical_compound
Animals
Humans
Urea
MYB
Castration
Molecular Biology
BRCA1 Protein
Nuclear Proteins
Prostatic Neoplasms
Cell Cycle Checkpoints
Cell Biology
Xenograft Model Antitumor Assays
Molecular biology
DNA-Binding Proteins
Androgen receptor
chemistry
Receptors, Androgen
Phthalazines
Poly(ADP-ribose) Polymerases
Carrier Proteins
DNA Damage
Subjects
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