Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development.
Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development.
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用于早期临床开发的DNA损伤反应的多个抑制剂的放射性增强图谱。
DOI：
10.1158/1535-7163.mct-20-0502
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发表时间：
2021-09
影响因子：
5.7
通讯作者：
O'Connor MJ
中科院分区：
文献类型：
--
作者：
Gill SJ;Wijnhoven PWG;Fok JHL;Lloyd RL;Cairns J;Armenia J;Nikkilä J;Lau A;Bakkenist CJ;Galbraith SM;Vens C;O'Connor MJ
放射治疗是一种有效的抗癌治疗方法，但需要与靶向药物相结合，在最大限度地发挥疗效的同时保留正常组织。在这里，我们评估了DNA损伤反应抑制剂奥拉帕利(PARP1/2)、Ceralasertib(ATR)、阿达伐替布(WEE1)、AZD0156(ATM)和KU-60648(DNA-PK)的放射增敏作用。我们进行了放射治疗联合筛查，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6个具有不同遗传/信号异常(包括TP53和ATM突变)的肺癌细胞系，并通过克隆形成实验评估了不同浓度的DDRI与固定的放射剂量联合使用。DDRI在联合放射治疗中的有效浓度低于单药疗效所需的浓度。在DDR缺乏的情况下，这有可能被进一步开发以增加治疗指数，我们证明低浓度的AZD0156优先敏化P53缺陷细胞。此外，在联合放射治疗中测试多种浓度的DDRI表明，奥拉帕利、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浓度的小幅增加，特别是KU-60648浓度的增加，会导致剂量增强的急剧增加。放射增敏分析可以提供与生物标记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。此外，多浓度测试证明了药物浓度和放射治疗效果之间的关系，这提供了有价值的见解，通过未来的体内验证，可以指导临床试验中的剂量递增策略。
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.