Radiosensitization Effect of Talazoparib, a Parp Inhibitor, on Glioblastoma Stem Cells Exposed to Low and High Linear Energy Transfer Radiation

Paul Lesueur (1, 2, 3) , François Chevalier (1, 2) , Elias A. El-Habr (4) , Marie-Pierre Junier (4) , Hervé Chneiweiss (4) , Laurent Castéra (3) , Etienne Müller (3) , Dinu Stefan (3) , Yannick Saintigny (1, 2)

1 LARIA - Laboratoire d'Accueil et de Recherche avec les Ions Accélérés
2 CIMAP - UMR 6252 - Centre de recherche sur les Ions, les MAtériaux et la Photonique
3 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
4 NPS-04 - Plasticité gliale et neuro-oncologie = Glial Plasticity

Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro. Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising.

Domains: Pharmacology; Cancer; Neurobiology

Paul Lesueur, François Chevalier, Elias A. El-Habr, Marie-Pierre Junier, Hervé Chneiweiss, et al.. Radiosensitization Effect of Talazoparib, a Parp Inhibitor, on Glioblastoma Stem Cells Exposed to Low and High Linear Energy Transfer Radiation. Scientific Reports, 2018, 8, pp.3664. ⟨10.1038/s41598-018-22022-4⟩. ⟨hal-01738585⟩