Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi. We pre-selected six lung cancer cell lines with different genetic/signaling aberrations (including mutations in TP53 and ATM ) and assessed multiple concentrations of DDRi in combination with a fixed radiotherapy dose by clonogenic assay. The effective concentration of DDRi in radiotherapy combinations is lower than that required for single-agent efficacy. This has the potential to be exploited further in the context of DDR deficiencies to increase therapeutic index and we demonstrate that low concentrations of AZD0156 preferentially sensitized p53-deficient cells. Moreover, testing multiple concentrations of DDRi in radiotherapy combinations indicated that olaparib, ceralasertib, and adavosertib have a desirable safety profile showing moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration. Small increases in concentration of AZD0156 and particularly KU-60648, however, result in steep increases in dose enhancement. Radiopotentiation profiling can inform on effective drug doses required for radiosensitization in relation to biomarkers, providing an opportunity to increase therapeutic index. Moreover, multiple concentration testing demonstrates a relationship between drug concentration and radiotherapy effect that provides valuable insights that, with future in vivo validation, can guide dose-escalation strategies in clinical trials.

中文翻译：

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用于早期临床开发的多种 DNA 损伤反应抑制剂的放射增强分析

放射疗法是一种有效的抗癌治疗方法，但需要与靶向药物联合使用，以最大限度地提高疗效，同时保留正常组织。在这里，我们评估了 DNA 损伤反应抑制剂 (DDRi) olaparib (PARP1/2)、ceralasertib (ATR)、adavosertib (WEE1)、AZD0156 (ATM) 和 KU-60648 (DNA-PK) 的放射增强谱。我们进行了放射治疗组合筛选并评估了药物浓度和细胞 DDR 缺陷如何影响 DDRi 的放射增强能力。我们预先选择了六种具有不同遗传/信号异常（包括 TP53 和 ATM 突变）的肺癌细胞系，并通过克隆形成测定评估了多种浓度的 DDRi 与固定放射治疗剂量的组合。放疗组合中 DDRi 的有效浓度低于单药疗效所需的浓度。这有可能在 DDR 缺陷的背景下进一步利用以增加治疗指数，我们证明低浓度的 AZD0156 优先使 p53 缺陷细胞敏感。此外，在放射治疗组合中测试多种浓度的 DDRi 表明，奥拉帕尼、ceralasertib 和 adavosertib 具有理想的安全性，显示随着抑制剂浓度的增加放射治疗剂量增加适度增加。然而，AZD0156 尤其是 KU-60648 浓度的小幅增加会导致剂量增加的急剧增加。放射增强分析可以告知与生物标志物相关的放射增敏所需的有效药物剂量，从而提供增加治疗指数的机会。而且，