Phosphorylated mTOR and YAP serve as prognostic markers and therapeutic targets in gliomas

Glioma is the most prevalent type of tumor in the brain and is comprised of grades I-IV, according to the WHO classification system. Grade IV glioma is also known as glioblastoma multiforme (GBM), the most malignant type of glioma. Glioma is characterized by a complex molecular background, and gene profiling studies have disclosed critical genetic events in human gliomas, which make targeted therapies the most promising therapeutic strategy. However, crosstalk between the targeted signaling pathways may hinder the efficacy of targeted therapies in gliomas. Therefore, it is necessary to identify effective markers to stratify patients for specific therapeutic procedures. Although several mechanisms have been proposed based on the crosstalk between PI3K/AKT/mTORC1 and Hippo/YAP pathways, the clinical significance of the two pathways has not yet been assessed in a combinatorial manner. In this study, we evaluated the two pathways in human glioma specimens and observed the positive correlation between protein levels of p-mTORS2448 and YAP in gliomas. The findings indicated that high expression of p-mTORS2448 and YAP correlated with poor overall survival of glioma patients. As p-mTORS2448 is a specific marker of mTORC1 activation, our results reveal a potential interaction between mTORC1 and YAP, which might functionally participate in the development and progression of gliomas. In support of this hypothesis, a combination of inhibitors targeting mTORC1 and YAP showed a better inhibitory effect on growth of glioma cell lines. Altogether, our work, for the first time, reveals that p-mTORS2448 and YAP can be used as markers of PI3K/AKT/mTORC1 and Hippo/YAP pathway activity to predict prognosis and are target candidates for personalized medicine.