ATP-site binding inhibitor effectively targets mTORC1 and mTORC2 complexes in glioblastoma

Neil,Jayson; Shannon,Craig; Mohan,Avinash; Laurent,Dimitri; Murali,Raj; Jhanwar-Uniyal,Meena

doi:10.3892/ijo.2015.3311

ATP-site binding inhibitor effectively targets mTORC1 and mTORC2 complexes in glioblastoma

Authors:
- Jayson Neil
- Craig Shannon
- Avinash Mohan
- Dimitri Laurent
- Raj Murali
- Meena Jhanwar-Uniyal
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Affiliations: Department of Neurosurgery, New York Medical College, Valhalla, NY 10595, USA
Published online on: December 28, 2015 https://doi.org/10.3892/ijo.2015.3311
Pages: 1045-1052

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Abstract

The PI3K-AKT-mTOR signaling axis is central to the transformed phenotype of glioblastoma (GBM) cells, due to frequent loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). The mechanistic target of rapamycin (mTOR) kinase is present in two cellular multi-protein complexes, mTORC1 and mTORC2, which have distinct subunit composition, substrates and mechanisms of action. Targeting the mTOR protein is a promising strategy for GBM therapy. However, neither of these complexes is fully inhibited by the allosteric inhibitor of mTOR, rapamycin or its analogs. Herein, we provide evidence that the combined inhibition of mTORC1/2, using the ATP-competitive binding inhibitor PP242, would effectively suppress GBM growth and dissemination as compared to an allosteric binding inhibitor of mTOR. GBM cells treated with PP242 demonstrated significantly decreased activation of mTORC1 and mTORC2, as shown by reduced phosphorylation of their substrate levels, p70 S6KThr389 and AKTSer473, respectively, in a dose-dependent manner. Furthermore, insulin induced activation of these kinases was abrogated by pretreatment with PP242 as compared with rapamycin. Unlike rapamycin, PP242 modestly activates extracellular regulated kinase (ERK1/2), as shown by expression of pERKThr202/Tyr204. Cell proliferation and S-phase entry of GBM cells was significantly suppressed by PP242, which was more pronounced compared to rapamycin treatment. Lastly, PP242 significantly suppressed the migration of GBM cells, which was associated with a change in cellular behavior rather than cytoskeleton loss. In conclusion, these results underscore the potential therapeutic use of the PP242, a novel ATP-competitive binding inhibitor of mTORC1/2 kinase, in suppression of GBM growth and dissemination.

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