title: [PARP inhibitors and radiotherapy: rational and prospects for a clinical use].
abstract: Poly(ADP-ribosyl)ation is a ubiquitous protein modification involved in the regulation of many cellular processes that is carried out by the poly(ADP-ribose) polymerase (PARP) family. The PARP-1, PARP-2 and PARP-3 are the only PARPs known to be activated by DNA damage. The absence of PARP-1 and PARP-2, that are both activated by DNA damage and participate in DNA damage repair processes, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD(+) at the enzyme's activity site can be used in BRCA-deficient cells as single agent therapies acting through the principle of synthetic lethality exploiting these cells deficient DNA double-strand break repair. Preclinical data showing an enhancement of the response of tumors to radiation has been documented for several PARP inhibitors. However, whether this is due exclusively to impaired DNA damage responses or whether tumor re-oxygenation contributes to this radio-sensitization via the vasoactive effects of the PARP inhibitors remains to be fully determined. These promising results have paved the way for the evaluation of PARP inhibitors in combination with radiotherapy in phase I and phase II clinical trials for malignant glioma, head and neck, and breast cancers. A number of challenges remain that are also reviewed in this article, including the optimization of treatment schedules for combined therapies and the validation of biomarkers that will identify which patients will most benefit from either PARP inhibitors in combination with radiotherapy.
authors.affiliation: Institut Curie, centre de recherche, bâtiment 110-112, centre universitaire d'Orsay, 91405 Orsay, France; Inserm U612, bâtiment 110-112, centre universitaire d'Orsay, 91405 Orsay, France; Département d'oncologie-radiothérapie, institut Curie, centre hospitalier, 26, rue d'Ulm, 75005 Paris, France. Electronic address: victoremmanuel.pernin@curie.net.
authors.forename: V
authors.initials: V
authors.lastname: Pernin
authors.affiliation: Inserm U1030, 114, rue Édouard-Vaillant, 94805 Villejuif, France; Cancer Campus Grand-Paris, institut Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Mégnin-Chanet
authors.affiliation: Institut Curie, centre de recherche, bâtiment 110-112, centre universitaire d'Orsay, 91405 Orsay, France; Inserm U612, bâtiment 110-112, centre universitaire d'Orsay, 91405 Orsay, France.
authors.forename: V
authors.initials: V
authors.lastname: Pennaneach
authors.affiliation: Département d'oncologie-radiothérapie, institut Curie, centre hospitalier, 26, rue d'Ulm, 75005 Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Fourquet
authors.affiliation: Département d'oncologie-radiothérapie, institut Curie, centre hospitalier, 26, rue d'Ulm, 75005 Paris, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Kirova
authors.affiliation: Institut Curie, centre de recherche, bâtiment 110-112, centre universitaire d'Orsay, 91405 Orsay, France; Inserm U612, bâtiment 110-112, centre universitaire d'Orsay, 91405 Orsay, France.
authors.forename: J
authors.initials: J
authors.lastname: Hall
mesh_terms: D003131:Combined Modality Therapy; D004260:DNA Repair; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases
keywords: BRCA1/2 mutations; Chemotherapy; Chimiothérapie; Inhibiteur de PARP; Létalité synthétique; Mutations BRCA1/2; PARP inhibitor; Radiotherapy; Radiothérapie; Synthetic lethality