Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity in vitro. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Individual subject-level data (Excel file).
Proposed model of combined targeting of pyrimidine synthesis in GSCs.ĭata file S1. Pairwise correlation analysis of pyrimidine pathway genes and gene enrichment analysis.įig. Combined targeting of pyrimidine synthesis inhibits GSC tumorigenesis in vivo.įig. Impact of targeted therapies on signal transduction pathways in vivo.įig. Sensitivity of GSCs to inhibitor treatments.įig. Combinatorial blockade of de novo pyrimidine synthesis in GSCs by the DHODH inhibitor teriflunomide and EGFR or PI3K inhibition.įig.
PTEN deletion promotes CAD S1859 phosphorylation through the PI3K-AKT-TORC1 but not the TORC2 pathway.įig. PTEN deletion promotes CAD S1859 phosphorylation through the PI3K-AKT pathway.įig. EGFR regulates CAD T456 phosphorylation through the MAPK-ERK pathway.įig. CAD and DHODH are essential for primary GSC maintenance.įig. DHODH regulates primary GSC growth and self-renewal.įig. CAD regulates primary GSC growth and self-renewal.įig. Validation of knockdown efficacy of shRNAs directed against CAD.įig. CAD S1859 and CAD T456 are important for GSC proliferation.įig. Identification of differential enhancer activation between GSCs and DGCs.įig.
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