Radiation-induced DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR) and nonhomologous end joining (NHEJ). Recently, it has been found that chronic tumor hypoxia compromises HR repair of DNA DSBs but activates the NHEJ protein DNAPK. We therefore hypothesized that inhibition of DNAPK can preferentially potentiate the sensitivity of chronically hypoxic cancer cells to radiation through contextual synthetic lethality in vivo . In this study, we investigated the impact of DNAPK inhibition by a novel selective DNAPK inhibitor, NU5455, on the repair of radiation-induced DNA DSBs in chronically hypoxic and nonhypoxic cells across a range of xenograft models. We found that NU5455 inhibited DSB repair following radiation in both chronically hypoxic and nonhypoxic tumor cells. Most importantly, the inhibitory effect was more pronounced in chronically hypoxic tumor cells than in nonhypoxic tumor cells. This is the first in vivo study to indicate that DNAPK inhibition may preferentially sensitize chronically hypoxic tumor cells to radiotherapy, suggesting a broader therapeutic window for transient DNAPK inhibition combined with radiotherapy. This article is featured in Highlights of This Issue, [p. 1497][1] [1]: /lookup/volpage/20/1497?iss=9

中文翻译：

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DNAPK 抑制优先损害异种移植模型中长期缺氧肿瘤细胞中辐射诱导的 DNA 双链断裂的修复


辐射引起的 DNA 双链断裂 (DSB) 可以通过同源重组 (HR) 和非同源末端连接 (NHEJ) 进行修复。最近发现，慢性肿瘤缺氧会损害DNA DSBs的HR修复，但会激活NHEJ蛋白DNAPK。因此，我们假设抑制 DNAPK 可以通过体内背景合成致死性优先增强慢性缺氧癌细胞对辐射的敏感性。在这项研究中，我们研究了一种新型选择性 DNAPK 抑制剂 NU5455 抑制 DNAPK 对一系列异种移植模型中长期缺氧和非缺氧细胞中辐射诱导的 DNA DSB 修复的影响。我们发现 NU5455 抑制长期缺氧和非缺氧肿瘤细胞放疗后的 DSB 修复。最重要的是，在长期缺氧的肿瘤细胞中的抑制作用比在非缺氧的肿瘤细胞中更明显。这是第一个体内研究表明DNAPK抑制可能优先使长期缺氧的肿瘤细胞对放射治疗敏感，这表明短暂的DNAPK抑制与放射治疗相结合具有更广泛的治疗窗口。本文收录于本期亮点，[p. 11]。 1497][1][1]：/lookup/volpage/20/1497?iss=9