Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA- PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts (PDXs) of melanoma brain metastases (M12, M15, M27). In clonogenic survival assays, peposertib augmented RT- induced killing of M12 cells at concentrations ≥100 nM, and a minimum of 16 h exposure allowed maximal sensitization. This information was integrated with pharmacokinetic modeling to define an optimal dosing regimen for peposertib of 125 mpk dosed just prior to and seven hours after irradiation. Using this drug dosing regimen in combination with 2.5 Gy x 5 fractions of radiation, significant prolongation in median survival was observed in M12-eGFP (104%; p=0.0015) and M15 (50%; p=0.03), while more limited effects were seen in M27 (16%, p=0.04). These data support the concept of developing peposertib as a radiosensitizer for brain metastases and provide a paradigm for integrating in vitro and pharmacokinetic data to define an optimal radiosensitizing regimen for potent DNA repair inhibitors.

中文翻译：

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DNA-PKcs 抑制剂 peposertib 的差异分布选择性地使患者来源的黑色素瘤脑转移异种移植物放射增敏

黑色素瘤脑转移的放射抗性限制了传统分割脑辐射在该疾病中的临床应用，而改善放射反应的策略可能会产生重大的临床影响。DNA 依赖性蛋白激酶 (DNA-PKcs) 的催化亚基对于修复辐射引起的 DNA 损伤至关重要，该激酶的抑制剂可对辐射敏感性产生有效影响。在这项研究中，在黑色素瘤脑转移瘤（M12、M15、M27）的患者来源异种移植物（PDX）中评估了 DNA-PKcs 抑制剂 peposertib 的放射增敏作用。在克隆形成存活测定中，peposertib 在浓度≥100 nM 时增强了 RT 诱导的 M12 细胞杀伤作用，并且至少 16 小时的暴露可实现最大敏化。该信息与药代动力学模型相结合，以确定在照射前和照射后 7 小时服用 125 mpk 的 peposertib 的最佳给药方案。使用该药物剂量方案与 2.5 Gy x 5 部分放射治疗相结合，在 M12-eGFP (104%; p=0.0015) 和 M15 (50%; p=0.03) 中观察到中位生存期显着延长，而效果更有限见于 M27（16%，p=0.04）。这些数据支持开发peposertib作为脑转移放射增敏剂的概念，并提供了整合体外和药代动力学数据的范例，以确定有效DNA修复抑制剂的最佳放射增敏方案。