LGG-15. COMBINED SUPPRESSION OF THE MTOR AND MAPK PATHWAYS INHIBITS CELL PROLIFERATION AND DECREASES VASCULARITY IN PEDIATRIC LOW GRADE GLIOMA. (23rd April 2019) - Arnold, Antje
Abstract: Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in five patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1 NF1mut, BT66_SV40 BRAF:KIAA1549, BT40 BRAFV600E, Res186 PTEN-/- and Res259 CDKN2A-/- . In all cell lines, trametinib treatment led to suppression of phospho-ERK at low levels (1-5nM; Western Blot). TAK228 treatment led to inhibition of mTORC1/2 in low nanomolar range. Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). We tested trametinib and TAK228 against the mutant BT40 BRAFV600E patient-derived xenograft cells in immunodeficient mice. Combination of TAK228 with trametinib showed greater antitumor activity than that of either mono-treatment in vivo . BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide a strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.