Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation. In a similar concentration-dependent manner, VX-984 treatment enhanced the radiosensitivity of each GBM cell line as defined by clonogenic analysis. As determined by γH2AX expression and neutral comet analyses, VX-984 inhibited the repair of radiation-induced DNA double-strand break in U251 and NSC11 GBM cells, suggesting that the VX-984-induced radiosensitization is mediated by an inhibition of DNA repair. Extending these results to an in vivo model, treatment of mice with VX-984 inhibited radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts, indicating that this compound crosses the blood–brain tumor barrier at sufficient concentrations. For mice bearing U251 or NSC11 brain tumors, VX-984 treatment alone had no significant effect on overall survival; radiation alone increased survival. The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM. Mol Cancer Ther; 17(6); 1207–16. ©2018 AACR.

中文翻译：

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DNA-PK 抑制剂 VX-984 可增强体外培养的胶质母细胞瘤细胞和原位异种移植物的放射敏感性

放射治疗是胶质母细胞瘤 (GBM) 的主要治疗方式。由于 DNA-PKcs 是修复辐射诱导的双链断裂 (DSB) 的关键因素，因此本研究评估了 VX-984（一种新型 DNA-PKcs 抑制剂）增强 GBM 细胞放射敏感性的潜力。在体外条件下用 VX-984 处理已建立的 GBM 细胞系 U251 和 GBM 干细胞样细胞 (GSC) 系 NSC11，导致对辐射诱导的 DNA-PKcs 磷酸化的浓度依赖性抑制。以类似的浓度依赖性方式，VX-984 处理增强了每个 GBM 细胞系的放射敏感性，如克隆分析所定义的。通过γH2AX 表达和中性彗星分析确定，VX-984 抑制 U251 和 NSC11 GBM 细胞中辐射诱导的 DNA 双链断裂的修复，表明 VX-984 诱导的放射增敏是通过抑制 DNA 修复介导的。将这些结果扩展到体内模型，用 VX-984 治疗小鼠可抑制原位脑肿瘤异种移植物中辐射诱导的 DNA-PKcs 磷酸化，表明该化合物以足够的浓度穿过血脑肿瘤屏障。对于携带 U251 或 NSC11 脑肿瘤的小鼠，单独使用 VX-984 治疗对总体存活率没有显着影响；单独放疗可以提高存活率。与对照和单独的辐射相比，接受联合方案的小鼠的存活率显着增加。这些结果表明 VX-984 增强了脑肿瘤异种移植物的放射敏感性，并表明它可能有益于 GBM 的治疗管理。摩尔癌症治疗; 17(6); 1207-16。