ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G 0 -G 1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53 -mutant tumors but not in TP53 -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53 -mutant, but not in TP53 -WT, PDXs. In plasmid-based reporter assays, GBM43 ( TP53 -mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53 -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53 -mutant cells to ATM inhibitor–mediated radiosensitization.

中文翻译：

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异常 ATM 信号传导和同源定向 DNA 修复是 p53 突变 GBM 对 AZD1390 介导的放射增敏的脆弱性

ATM 是放射反应的关键介质，ATM 的药理学抑制是肿瘤放射增敏的合理策略。AZD1390 是一种脑渗透性 ATM 抑制剂和有效的放射增敏剂。这项研究评估了放射增敏效应的范围以及TP53一组中的突变状态IDH1野生型（WT）胶质母细胞瘤（GBM）患者来源的异种移植物（PDX）。AZD1390 抑制辐射诱导的 ATM 信号传导，消除 G0-G1阻滞，并在体外促进 p53 突变 GBM 中的促凋亡反应。在使用 10 个原位 GBM 模型的临床前试验中，AZD1390/RT 在一组患者中提供了益处TP53-突变肿瘤但不存在于TP53-WT PDX。在机制研究中，观察到内源性 DNA 损伤和组成型 ATM 信号传导增加TP53-突变体，但不存在TP53-WT、PDX。在基于质粒的报告基因检测中，GBM43 (TP53-突变体）与 GBM14 (p53-WT) 相比显示出更高的 DNA 修复能力，而 AZD1390 处理则通过阻止 RAD51 卸载来特异性抑制同源重组 (HR) 效率。此外，显性失活的过度表达TP53(p53DD) 构建体导致 GBM14 中基础 ATM 信号传导、HR 活性和 AZD1390 介导的放射增敏增强。分析 TCGA 的 RNA-seq 数据显示，HR 通路基因在TP53-突变人类GBM。总之，我们的结果表明，基础 ATM 信号传导的增加和对 HR 的依赖性的增强代表了一种独特的易感性。TP53-突变细胞对ATM抑制剂介导的放射增敏。