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J Histochem Cytochem. 2018 Jun;66(6):403-414. doi: 10.1369/0022155417750838. Epub 2018 Jan 12.

Overexpression of mTOR and p(240-244)S6 in IDH1 Wild-Type Human Glioblastomas Is Predictive of Low Survival.

Author information

1
International Research Center, A.C.Camargo Cancer Center, National Institute of Science and Technology in Oncogenomics, São Paulo, Brazil.
2
Pathology Department, A.C.Camargo Cancer Center, National Institute of Science and Technology in Oncogenomics, São Paulo, Brazil.
3
Institute Pelé-Pequeno Príncipe for Research on Pediatric Cancer, Curitiba, Brazil.

Abstract

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.

KEYWORDS:

TOR serine-threonine kinases; biomarkers; glioblastoma; glioma; mechanistic target of rapamycin complex 1; phosphatidylinositol 3-kinases; phosphorylation; ribosomal protein S6 kinases; survival rate

PMID:
29328863
PMCID:
PMC5977438
[Available on 2019-06-01]
DOI:
10.1369/0022155417750838

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