Overexpression of mTOR and p(240-244)S6 in IDH1 Wild-Type Human Glioblastomas Is Predictive of Low Survival
Overexpression of mTOR and p(240-244)S6 in IDH1 Wild-Type Human Glioblastomas Is Predictive of Low Survival
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DOI：
10.1369/0022155417750838
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发表时间：
2018-06-01
影响因子：
3.2
通讯作者：
Maroso Hajj, Glaucia Noeli
中科院分区：
文献类型：
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作者：
Machado, Luis Eduardo;Alvarenga, Arthur William;Maroso Hajj, Glaucia Noeli
PI3K/Akt/mTOR通路激活是高级别胶质瘤的一个标志，这促使临床试验使用PI3K和mTOR抑制剂。然而，最初试验中糟糕的结果表明，此类药物需要更好的患者特征分析。因此，对mTOR复合体的准确和可重复性的监测可以改进治疗策略。在这项工作中，我们评估了mTOR、Raptor和rpS6在195例人脑星形细胞瘤和30例正常脑组织中的表达和磷酸化。MTOR在胶质母细胞瘤中的表达增加，而mTOR的磷酸化、Raptor的表达以及rpS6的表达和磷酸化在不同级别之间相似。有趣的是，总mTOR和磷酸化mTOR以及磷酸化rpS6(残基240-244)的过度表达仅与野生型IDH1胶质母细胞瘤相关。MTOR的表达和磷酸化以及rpS6在240-244位残基的磷酸化与胶质母细胞瘤的预后不良有关。我们的结果表明，mTOR和rpS6可以作为PI3K-mTOR通路过度激活的标志物，并且是胶质母细胞瘤总存活率的预测因子。因此，我们的研究表明，携带IDH1野生型胶质母细胞瘤的患者可能从针对mTOR的靶向治疗中受益增加。
PI3K/Akt/mTOR pathway activation is a hallmark of high-grade gliomas, which prompted clinical trials for the use of PI3K and mTOR inhibitors. However, the poor results in the original trials suggested that better patient profiling was needed for such drugs. Thus, accurate and reproducible monitoring of mTOR complexes can lead to improved therapeutic strategies. In this work, we evaluated the expression and phosphorylation of mTOR, RAPTOR, and rpS6 in 195 human astrocytomas and 30 normal brain tissue samples. The expression of mTOR increased in glioblastomas, whereas mTOR phosphorylation, expression of RAPTOR, and expression and phosphorylation of rpS6 were similar between grades. Interestingly, the overexpression of total and phosphorylated mTOR as well as phosphorylated rpS6 (residues 240-244) were associated with wild-type IDH1 only glioblastomas. The expression and phosphorylation of mTOR and phosphorylation of rpS6 at residues 240-244 were associated with a worse prognosis in glioblastomas. Our results suggest that mTOR and rpS6 could be used as markers of overactivation of the PI3K-mTOR pathway and are predictive factors for overall survival in glioblastomas. Our study thus suggests that patients who harbor IDH1 wild-type glioblastomas might have increased benefit from targeted therapy against mTOR.