多聚ADP核糖聚合酶和共济失调-毛细血管扩张症联合突变/Rad3相关抑制靶点共济失调-毛细血管扩张-突变缺陷型肺癌细胞

多聚ADP核糖聚合酶和共济失调-毛细血管扩张症联合突变/Rad3相关抑制靶点共济失调-毛细血管扩张-突变缺陷型肺癌细胞

英国癌症杂志　引用文献下载

背景技术

据报道，多达40%的肺腺癌缺乏共济失调-毛细血管扩张症。(自动取款机)蛋白表达我们询问ATM缺乏的肺癌细胞对多聚ADP核糖聚合酶(PARP)抑制剂是否敏感，并确定了olaparib对ATM缺乏的A 549细胞的作用机制。

方法

我们从肿瘤药物敏感基因组学(GDSC)项目中分析了肺腺癌细胞对奥拉帕瑞布和他拉唑比的药物敏感性数据。我们用CRISPR/Cas9技术从A 549肺腺癌细胞中删除了ATM，并测定了奥拉帕瑞布和ATR/Rad3相关抑制剂VE-821对细胞活力的影响。

结果

集成电路50奥拉帕林和他拉唑巴利值均与自动取款机肺腺癌细胞系的mRNA水平及基因扩增状况。ATM突变与IC显著减少有关。50对于olaparib来说，Talazoparib也有类似的趋势。缺失ATM的A 549细胞对电离辐射和olaparib敏感。olaparib诱导atm缺陷细胞DNA损伤标记磷酸化和可逆G2阻滞，而olaparib和VE-821联合作用诱导细胞死亡。

结论

以ATM缺乏为特征的肿瘤患者可以从PARP抑制剂和ATR抑制剂联合治疗中获益。

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