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

Paul Lesueur,François Chevalier,Yannick Saintigny,Marie-Pierre Junier,Laurent Castera,Hervé Chneiweiss,Etienne Müller,Elias A El-Habr,Dinu Stefan

doi:10.1038/s41598-018-22022-4

Abstract

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.

Highlights

Despite this multimodality treatment, the median overall survival is limited to 14.6 months[2]
The exons of 69 genes implicated in homologous recombination were sequenced for each cell line in order to identify deleterious mutations of genes involved in DNA repair, the defects of which could lead to enhanced anticancer effects or synthetic lethality when cells are exposed to PARP inhibitors (PARPi) and irradiation
We confirmed that the phosphatase and tensin homolog (PTEN) gene was deleted in the R633 cell line, as described, with no expression by western blot analysis[18] (Table 1)

Summary

Introduction

The median overall survival is limited to 14.6 months[2]. Patient survival posits that the GSC population responds differently to temozolomide or radiation therapy than the nonstem cell population. PARP inhibitors (PARPis) first entered clinical trials in 2003 in combination with the monomethylating agent temozolomide for patients with advanced solid tumors[8,9]. Their development has been accelerated since the concept of synthetic lethality appeared in homologous recombination-deficient cells that were exposed to PARPis[10]. Dungey et al showed that the radiosensitizing effect of PARPis is S-phase dependent[11] This replication-dependent mechanism allows adjacent healthy tissues to be protected while sensitizing highly proliferative tumors. Enhancement ratios ranged between 1.08 and 1.93 in in vitro studies[9], and the only published phase I study assessed the safety of the combination PARPi (veliparib) and irradiation[12]

Methods

Results

Conclusion