Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models
Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models
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DOI：
10.1172/jci142158
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发表时间：
2021-01-04
影响因子：
15.9
通讯作者：
Kirsch, David G.
中科院分区：
文献类型：
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作者：
Deland, Katherine;Starr, Bryce F.;Kirsch, David G.
弥漫性固有桥脑胶质瘤(DIPG)比任何其他类型的脑肿瘤导致更多的儿童死亡。尽管临床试验测试了许多化疗药物，姑息放射治疗仍然是标准治疗方法。在这里，我们利用Cre/loxP技术来证明在DIPG的原始小鼠模型中删除毛细血管扩张性共济失调突变(ATM)可以增强肿瘤的放射敏感性。ATM基因缺失可改善p53缺失的小鼠放疗后的存活率，但不能改善p53野生型胶质瘤的存活率。与DIPG患者相似，携带p5.3野生型肿瘤的小鼠在放射治疗后存活率提高，与ATM缺失无关。原代p53野生型肿瘤细胞系照射后可诱导促凋亡基因表达，并抑制NAD(P)H-Quinone脱氢酶1(NQO1)的表达。缺失P53和Ink4a/Arf的肿瘤细胞表达最高水平的Nqca，且对辐射的抵抗力最强，但ATM的缺失增强了辐射反应。这些结果表明，肿瘤基因型别可能决定放疗期间抑制ATM是否将是治疗DIPGs的有效临床方法。
Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p5.3 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqca and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.