Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer

Sci Signal. 2014 May 20;7(326):ra47. doi: 10.1126/scisignal.2005070.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Castration
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • DNA Damage*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phthalazines / pharmacology*
  • Piperazines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-myb / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myb / genetics
  • Proto-Oncogene Proteins c-myb / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Thiophenes / pharmacology*
  • Urea / analogs & derivatives*
  • Urea / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
  • BRCA1 Protein
  • BRCA1 protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins c-myb
  • Receptors, Androgen
  • TOPBP1 protein, human
  • Thiophenes
  • Urea
  • Poly(ADP-ribose) Polymerases
  • olaparib

Associated data

  • GEO/GSE49287