Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells.
Xiuxing WangKailin YangQiulian WuLeo J Y KimAndrew R MortonRyan N GimpleBriana C PragerYu ShiWenchao ZhouShruti BhargavaZhe ZhuLi JiangWeiwei TaoZhixin QiuLinjie ZhaoGuoxing ZhangXiqing LiSameer AgnihotriPaul S MischelStephen C MackShideng BaoJeremy N RichPublished in: Science translational medicine (2020)
Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo 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. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. 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. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
Keyphrases
- poor prognosis
- stem cells
- long non coding rna
- coronary artery disease
- cancer therapy
- cancer stem cells
- small cell lung cancer
- type diabetes
- cell proliferation
- genome wide
- cell therapy
- drug delivery
- heavy metals
- epidermal growth factor receptor
- bone marrow
- copy number
- risk assessment
- transcription factor
- single molecule
- insulin resistance
- signaling pathway
- binding protein