Journal article
Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells
Science translational medicine, Vol.11(504), 4972
08/07/2019
DOI: 10.1126/scitranslmed.aau4972
PMCID: PMC7568232
PMID: 31391321
Abstract
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.
Details
- Title: Subtitle
- Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells
- Creators
- Xiuxing Wang - University of California San DiegoKailin Yang - Cleveland ClinicQiulian Wu - University of California San DiegoLeo J. Y. Kim - Case Western Reserve UniversityAndrew R. Morton - Case Western Reserve UniversityRyan C. Gimple - University of California San DiegoBriana C. Prager - Cleveland Clinic Lerner College of MedicineYu Shi - Army Medical UniversityWenchao Zhou - Cleveland Clinic Lerner College of MedicineShruti Bhargava - University of California San DiegoZhe Zhu - University of California San DiegoLi Jiang - University of California San DiegoWeiwei Tao - Cleveland Clinic Lerner College of MedicineZhixin Qiu - University of California San DiegoLinjie Zhao - University of California San DiegoGuoxing Zhang - Univ Calif San Diego, Dept Med, Div Regenerat Med, La Jolla, CA 92037 USAXiqing Li - University of California San DiegoSameer Agnihotri - Children's Hospital of PittsburghPaul S. Mischel - Ludwig Cancer ResearchStephen C. Mack - Baylor College of MedicineShideng Bao - Cleveland Clinic Lerner College of MedicineJeremy N. Rich - University of California San Diego
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.11(504), 4972
- DOI
- 10.1126/scitranslmed.aau4972
- PMID
- 31391321
- PMCID
- PMC7568232
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Publisher
- Amer Assoc Advancement Science
- Number of pages
- 14
- Grant note
- CA197718; CA154130; CA169117; CA171652; NS087913; NS089272; CA184090; NS091080; NS099175; NS073831 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 08/07/2019
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696582802771
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