文章：

ATM状态在患者来源异种移植模型中驱动对DNA损伤反应抑制剂敏感性的相关性

Relevance of ATM Status in Driving Sensitivity to DNA Damage Response Inhibitors in Patient-Derived Xenograft Models

原文发布日期：21 August 2023

DOI: 10.3390/cancers15164195

类型: Article

开放获取: 是

英文摘要：

Ataxia-telangiectasia mutated gene (ATM) is a key component of the DNA damage response (DDR) and double-strand break repair pathway. The functional loss of ATM (ATM deficiency) is hypothesised to enhance sensitivity to DDR inhibitors (DDRi). Whole-exome sequencing (WES), immunohistochemistry (IHC), and Western blotting (WB) were used to characterise the baseline ATM status across a panel of ATM mutated patient-derived xenograft (PDX) models from a range of tumour types. Antitumour efficacy was assessed with poly(ADP-ribose)polymerase (PARP, olaparib), ataxia- telangiectasia and rad3-related protein (ATR, AZD6738), and DNA-dependent protein kinase (DNA-PK, AZD7648) inhibitors as a monotherapy or in combination to associate responses with ATM status. Biallelic truncation/frameshift ATM mutations were linked to ATM protein loss while monoallelic or missense mutations, including the clinically relevant recurrent R3008H mutation, did not confer ATM protein loss by IHC. DDRi agents showed a mixed response across the PDX’s but with a general trend toward greater activity, particularly in combination in models with biallelic ATM mutation and protein loss. A PDX with an ATM splice-site mutation, 2127T > C, with a high relative baseline ATM expression and KAP1 phosphorylation responded to all DDRi treatments. These data highlight the heterogeneity and complexity in describing targetable ATM-deficiencies and the fact that current patient selection biomarker methods remain imperfect; although, complete ATM loss was best able to enrich for DDRi sensitivity.

摘要翻译： 

共济失调毛细血管扩张突变基因（ATM）是DNA损伤应答（DDR）及双链断裂修复通路的关键组分。ATM功能缺失（ATM缺陷）被推测可增强对DDR抑制剂（DDRi）的敏感性。本研究采用全外显子组测序（WES）、免疫组织化学（IHC）和蛋白质印迹法（WB）对一组涵盖多种肿瘤类型的ATM突变患者来源异种移植（PDX）模型进行基线ATM状态表征。通过聚腺苷二磷酸核糖聚合酶（PARP，奥拉帕利）、共济失调毛细血管扩张及Rad3相关蛋白（ATR，AZD6738）和DNA依赖性蛋白激酶（DNA-PK，AZD7648）抑制剂单药或联合用药评估抗肿瘤疗效，并将治疗反应与ATM状态进行关联分析。双等位基因截短/移码ATM突变与ATM蛋白缺失相关，而单等位基因或错义突变（包括临床相关的复发性R3008H突变）在IHC检测中未导致ATM蛋白缺失。DDRi药物在PDX模型中呈现差异反应，但总体趋势显示在双等位基因ATM突变伴蛋白缺失的模型中活性更强，联合用药时尤为显著。携带ATM剪接位点突变（2127T>C）的PDX模型虽具有较高的基线ATM表达和KAP1磷酸化水平，仍对所有DDRi治疗产生应答。这些数据揭示了可靶向ATM缺陷的异质性与复杂性，表明当前患者筛选的生物标志物方法仍不完善；尽管完全性ATM缺失最能有效富集对DDRi敏感的群体。

原文链接：

Relevance of ATM Status in Driving Sensitivity to DNA Damage Response Inhibitors in Patient-Derived Xenograft Models