Treatment refractory glioblastoma (GBM) remains a major clinical problem globally, and targeted therapies in GBM have not been promising to date. The Cancer Genome Atlas integrative analysis of GBM reported the striking finding of genetic alterations in the p53 and PI3K pathways in more than 80% of GBMs. Given the role of these pathways in making cell-fate decisions and responding to genotoxic stress, we investigated the reliance of these two pathways in mediating radiation resistance. We selected a panel of GBM cell lines and glioma stem cells (GSC) with wild-type TP53 (p53-wt) and mutant TP53, mutations known to interfere with p53 functionality (p53-mt). Cell lines were treated with a brain permeable inhibitor of P-Akt (ser473), phosphatidylinositol ether lipid analogue (PIA), with and without radiation treatment. Sensitivity to treatment was measured using Annexin-V/PI flow cytometry and Western blot analysis for the markers of apoptotic signaling, alkaline COMET assay. All results were verified in p53 isogenic cell lines. p53-mt cell lines were selectively radiosensitized by PIA. This radiosensitization effect corresponded with an increase in DNA damage and a decrease in DNA-PKcs levels. TP53 silencing in p53-wt cells showed a similar response as the p53-mt cells. In addition, the radiosensitization effects of Akt inhibition were not observed in normal human astrocytes, suggesting that this treatment strategy could have limited off-target effects. We demonstrate that the inhibition of the PI3K/Akt pathway by PIA radiosensitizes p53-mt cells by antagonizing DNA repair. In principle, this strategy could provide a large therapeutic window for the treatment of TP53-mutant tumors. Mol Cancer Ther; 17(2); 336–46. ©2017 AACR. See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

中文翻译：

---

缺乏组成型活性 DNA 修复使胶质母细胞瘤对 Akt 抑制敏感，并以 p53 依赖性方式通过放射治疗诱导合成致死

治疗难治性胶质母细胞瘤 (GBM) 仍然是全球主要的临床问题，迄今为止，GBM 的靶向治疗并不乐观。GBM 的癌症基因组图谱综合分析报告了超过 80% 的 GBM 中 p53 和 PI3K 通路基因改变的惊人发现。鉴于这些途径在做出细胞命运决定和应对基因毒性应激方面的作用，我们研究了这两种途径在介导辐射抗性方面的依赖。我们选择了一组具有野生型 TP53 (p53-wt) 和突变型 TP53 的 GBM 细胞系和神经胶质瘤干细胞 (GSC)，已知突变会干扰 p53 功能 (p53-mt)。细胞系用 P-Akt (ser473) 的脑渗透抑制剂、磷脂酰肌醇醚脂质类似物 (PIA) 处理，有和没有放射治疗。使用膜联蛋白-V/PI 流式细胞术和蛋白质印迹分析对细胞凋亡信号转导的标记物、碱性 COMET 测定法测量对治疗的敏感性。所有结果均在 p53 同基因细胞系中得到验证。p53-mt 细胞系被 PIA 选择性地放射增敏。这种放射增敏效应与 DNA 损伤的增加和 DNA-PKcs 水平的降低相对应。p53-wt 细胞中的 TP53 沉默显示出与 p53-mt 细胞相似的反应。此外，在正常人星形胶质细胞中未观察到 Akt 抑制的放射增敏作用，表明这种治疗策略可能具有有限的脱靶效应。我们证明 PIA 对 PI3K/Akt 通路的抑制通过拮抗 DNA 修复使 p53-mt 细胞敏感。原则上，这种策略可以为 TP53 突变肿瘤的治疗提供一个大的治疗窗口。摩尔癌症治疗; 17(2); 336-46。©2017 AACR。请参阅此 MCT 焦点部分中的所有文章，“放射肿瘤学中的发育疗法”。