Co-Targeting MAP Kinase and Pi3K-Akt-mTOR Pathways in Meningioma: Preclinical Study of Alpelisib and Trametinib

SIMPLE SUMMARY: Multi recurrent or high-grade meningiomas remain an unmet medical need in neuro-oncology. Several studies have highlighted the potential therapeutic efficacy of mTor inhibitors to control tumoral growth of meningiomas. However, a positive feedback on AKT oncogenic pathway from these drugs may explain the modest success. Our aim was to target Pi3kinase upstream mTor, and MAP kinase pathway, overactivated in meningiomas, alone or in combined targeting in comparison to mTor targeting. Our in vitro results obtained on three meningioma cell lines and on a large series of fresh human meningiomas, including 35 WHO grade 1, 23 grade 2, and five grade 3, showed that co-targeting Pi3kinase and MAP kinase seemed promising, opening new therapeutic strategies in these tumors. ABSTRACT: Recurrent or high-grade meningiomas are an unmet medical need. Recently, we demonstrated that targeting mTOR by everolimus was relevant both in vitro and in humans. However, everolimus induces an AKT activation that may impact the anti-proliferative effect of the drug. Moreover, the MAP kinase pathway was shown to be involved in meningioma tumorigenesis. We therefore targeted both the Pi3k-AKT-mTOR and MAP kinase pathways by using combinations of the Pi3k inhibitor alpelisib and the MEK inhibitor trametinib. Our study was performed in vitro on the human meningioma cell lines and on a large series of primary cultures providing from 63 freshly operated meningiomas including 35 WHO grade 1, 23 grade 2, and five grade 3, half of which presented a NF2 genomic alteration. Alpelisib induced a higher inhibitory effect on cell viability and proliferation than everolimus in all cell lines and 32 randomly selected tumors no matter the genomic status, the histological subtype or grade. Trametinib also strongly inhibited cell proliferation and induced AKT activation. Combined treatment with alpelisib plus trametinib reversed the AKT activation induced by trametinib and induced an additive inhibitory effect irrespective of the cell lines or tumor features. Co-targeting pathways seems promising and may be considered particularly for aggressive meningioma.