title: Synergistic Effect of Trabectedin and Olaparib Combination Regimen in Breast Cancer Cell Lines.
abstract: OBJECTIVE
  Trabectedin induces synthetic lethality in tumor cells carrying defects in homologous recombinant DNA repair. We evaluated the effect of concomitant inhibition of nucleotide-excision repair and poly (ADP-ribose) polymerase (PARP) activity with trabectedin and PARP inhibitors, respectively, and whether the synthetic lethality effect had the potential for a synergistic effect in breast cancer cell lines. Additionally, we investigated if this approach remained effective in BRCA1-positive breast tumor cells.
  
  
  METHODS
  We have evaluated the in vitro synergistic effect of combinations of trabectedin and three different PARP inhibitors (veliparib, olaparib, and iniparib) in four breast cancer cell lines, each presenting a different BRCA1 genetic background. Antiproliferative activity, DNA damage, cell cycle perturbations and poly(ADP-ribosyl)ation were assessed by MTT assay, comet assay, flow cytometry and western blot, respectively.
  
  
  RESULTS
  The combination of trabectedin and olaparib was synergistic in all the breast cancer cell lines tested. Our data indicated that the synergy persisted regardless of the BRCA1 status of the tumor cells. Combination treatment was associated with a strong accumulation of double-stranded DNA breaks, G2/M arrest, and apoptotic cell death. Synergistic effects were not observed when trabectedin was combined with veliparib or iniparib.
  
  
  CONCLUSIONS
  Collectively, our results indicate that the combination of trabectedin and olaparib induces an artificial synthetic lethality effect that can be used to kill breast cancer cells, independent of BRCA1 status.
authors.affiliation: Cell Biology and Pharmacogenomics Department, PharmaMar S.A., Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Ávila-Arroyo
authors.affiliation: Cell Biology and Pharmacogenomics Department, PharmaMar S.A., Madrid, Spain.
authors.forename: Gema Santamaría
authors.initials: GS
authors.lastname: Nuñez
authors.affiliation: Cell Biology and Pharmacogenomics Department, PharmaMar S.A., Madrid, Spain.
authors.forename: Luis Francisco
authors.initials: LF
authors.lastname: García-Fernández
authors.affiliation: Cell Biology and Pharmacogenomics Department, PharmaMar S.A., Madrid, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
keywords: BRCA1 protein; Breast neoplasms; Drug combinations; Olaparib; Trabectedin