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 μmol/L) or AG14361 (0.4 μmol/L) and dramatically lower as compared with second-generation inhibitors such as PJ34 (5 μmol/L). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (∼1 hour) and at pharmacologically 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. Mol Cancer Ther; 17(10); 2206–16. ©2018 AACR.

中文翻译：

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BMN673 抑制 Parp1 通过扰乱处理 DNA 双链断裂的修复途径的平衡，有效地使细胞对放疗敏感

Parp 抑制剂 (Parpi) 通常用作治疗具有同源重组修复 (HRR) 缺陷的肿瘤的单一药物，但由于通常观察到的适度放射增敏作用，并未广泛考虑与放疗 (RT) 联用。BMN673 是最近开发的 Parpi 之一，已被证明可介导细胞对甲基化剂的强烈敏感性。在这里，我们探索了 BMN673 放射致敏杀伤的机制，旨在将其与 RT 相结合。我们证明 BMN673 在显着低于奥拉帕尼 (3 μmol/L) 或 AG14361 (0.4 μmol/L) 的浓度 (50 nmol/L) 和显着低于第二代抑制剂如 PJ34 (5 μmol/L) L)。尤其，BMN673 放射增敏在令人惊讶的短接触时间（约 1 小时）和体内药理学可达到的浓度后达到峰值。BMN673 对 DNA 双链断裂 (DSB) 处理产生一系列复杂的影响，包括在高剂量电离辐射 (IR) 下抑制经典的非同源末端连接 (cNHEJ) 和替代末端连接 (altEJ) 通路。BMN673 增强了 DSB 的切除，并有利于低临床相关 IR 剂量下的 HRR 和 altEJ。这些影响的综合结果是废除 DSB 处理的内在平衡，最终形成支持放射增敏的染色体易位。我们的观察为探索 BMN673 与放疗联合治疗各种癌症的固有益处的临床试验铺平了道路。摩尔癌症治疗; 17(10); 2206-16。©2018 AACR。