Combined inhibition by PRMT5 and MAT2A demonstrates a strong synthetic lethality in MTAP homozygous-deficient glioma models.

Abstract

The intra- and intertumoral heterogeneity of gliomas present major challenges to effective chemotherapy. This study explored the combined effects of PRMT5 and MAT2A inhibitors on glioma progression. The expression of drug targets was determined in cell models using western blotting and immunofluorescence assay. CCK-8, colony-formation, EdU fluorescence, and flow cytometry cell cycle assays were conducted to assess the effect of the drugs on cell proliferation. Additionally, TUNEL fluorescence assay, flow cytometry apoptosis assay, western blotting, and comet assay were used to evaluate drug-induced apoptosis and DNA damage. Immunohistochemistry was used to validate the effect of the drugs in a 3D glioma organoid model. Patient-derived orthotopic xenograft models were used for in vivo efficacy evaluations. Lastly, transcriptome sequencing was used to elucidate the mechanism of action of the drugs, which was confirmed using western blotting. In phenotypic experiments, PRMT5 inhibitors reduced SDMA levels, inhibited cell proliferation, and promoted apoptosis in glioma models. The combination of PRMT5 inhibitors with MAT2A inhibitors enhanced synthetic lethality, leading to more potent antitumor effects. In vivo studies demonstrated that the drug combination significantly inhibited tumor growth and prolonged survival time. Our study proved the combination of PRMT5 and MAT2A inhibitors may induce synthetic lethality by downregulating the PI3K-AKT pathway, indicating the potential of this approach in treating gliomas.