[From poly(ADP-ribose) Discovery to PARP Inhibitors in Cancer Therapy]

Bull Cancer. 2015 Oct;102(10):863-73. doi: 10.1016/j.bulcan.2015.07.012. Epub 2015 Sep 15.
[Article in French]

Abstract

Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymerases. PARP-1 is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of their repair, contributing to the maintenance of genome integrity and cell survival. The fact that PARP inhibition impairs efficacy of break repair has been exploited as anticancer strategies to potentiate the cytotoxicity of anticancer drugs and radiotherapy. Numerous clinical trials based on this innovative approach are in progress. PARP inhibition has also proved to be exquisitely efficient to kill tumour cells deficient in double strand break repair by homologous recombination, such as cells mutated for the breast cancer early onset genes BRCA1 or BRCA2, by synthetic lethality. Several phase III clinical trials are in progress for the treatment of breast and ovarian cancers with BRCA mutations and the PARP inhibitor olaparib has just been approved for advanced ovarian cancers with germline BRCA mutation. This review recapitulates the history from the discovery of poly(ADP-ribosyl)ation reaction to the promising therapeutic applications of its inhibition in innovating anticancer strategies. Benefits, hopes and obstacles are discussed.

Keywords: BRCA1/2; Chemo- and radiotherapy; Chimio- et radiothérapie; DNA repair; Inhibiteurs PARP; Létalité synthétique; PARP inhibitors; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) polymérase; Réparation de l’ADN; Synthetic lethality.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Clinical Trials, Phase III as Topic
  • DNA Breaks, Double-Stranded
  • DNA Repair / drug effects*
  • Drug Discovery
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Humans
  • Mutation
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Poly(ADP-ribose) Polymerases / physiology

Substances

  • Antineoplastic Agents
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • olaparib