Inhibition of Parp1 by BMN673 Effectively Sensitizes Cells to Radiotherapy by Upsetting the Balance of Repair Pathways Processing DNA Double-Strand Breaks

摘要

Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy (RT) is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here, we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with RT. We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50 nmol/L) than olaparib (3 mu mol/L) or AG14361 (0.4 mu mol/L) and dramatically lower as compared with second-generation inhibitors such as PJ34 (5 mu mol/L). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (similar to 1 hour) and at pharmaco-logically achievable concentrations in vivo. BMN673 exerts a complex set of effects on DNA double-strand break (DSB) processing, including inhibition of classic nonhomologous end-joining (cNHEJ) and alternative end-joining (altEJ) pathway at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer. (C) 2018 AACR.