title: Activity of trabectedin and the PARP inhibitor rucaparib in soft-tissue sarcomas.
abstract: Trabectedin has recently been approved in the USA and in Europe for advanced soft-tissue sarcoma patients who have been treated with anthracycline-based chemotherapy without success. The mechanism of action of trabectedin depends on the status of both the nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways. Trabectedin results in DNA double-strand breaks. We hypothesized that PARP-1 inhibition is able to perpetuate trabectedin-induced DNA damage.
  
  
  
  We explored the effects of combining a PARP inhibitor (rucaparib) and trabectedin in a large panel of soft-tissue sarcoma (STS) cell lines and in a mouse model of dedifferentiated liposarcoma.
  
  
  
  The combination of rucaparib and trabectedin in vitro was synergistic, inhibited cell proliferation, induced apoptosis, and accumulated in the G2/M phase of the cell cycle with higher efficacy than either single agent alone. The combination also resulted in enhanced γH2AX intranuclear accumulation as a result of DNA damage induction. In vivo, the combination of trabectedin and rucaparib significantly enhanced progression-free survival with an increased percentage of tumor necrosis.
  
  
  
  The combination of PARP inhibitor and trabectedin is beneficial in pre-clinical models of soft-tissue sarcoma and deserves further exploration in the clinical setting.
authors.affiliation: INSERM ACTION U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France.|Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Laroche
authors.affiliation: INSERM ACTION U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France.|Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Chaire
authors.affiliation: Sarcoma Unit, Institut Bergonié, Bordeaux, France.|Department of Pathology, Institut Bergonié, Bordeaux, France.
authors.forename: François
authors.initials: F
authors.lastname: Le Loarer
authors.affiliation: University of Bordeaux, Bordeaux, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Algéo
authors.affiliation: INSERM ACTION U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France.|Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rey
authors.affiliation: INSERM ACTION U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France.|Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tran
authors.affiliation: INSERM ACTION U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France.|Sarcoma Unit, Institut Bergonié, Bordeaux, France.
authors.forename: Carlo
authors.initials: C
authors.lastname: Lucchesi
authors.affiliation: INSERM ACTION U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France. a.italiano@bordeaux.unicancer.fr.|Sarcoma Unit, Institut Bergonié, Bordeaux, France. a.italiano@bordeaux.unicancer.fr.|University of Bordeaux, Bordeaux, France. a.italiano@bordeaux.unicancer.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004260:DNA Repair; D004149:Dioxoles / Q000009:adverse effects / Q000627:therapeutic use*; D004357:Drug Synergism; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D012509:Sarcoma / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000009:adverse effects / Q000627:therapeutic use*; D000077606:Trabectedin
chemical_list: D004149:Dioxoles; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D044005:Tetrahydroisoquinolines; C531549:rucaparib; D000077606:Trabectedin
keywords: PARP; Sarcomas; Synergy; Trabectedin