ArticleCancer cell2022
De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma.
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Article in Cancer cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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91citing papers in PubMed
9.6field-weighted citation impact, top 1% of its field
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Who cites it
91 citing papers in PubMed, 118 citations in OpenAlex.
- DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells.Nature chemical biology · 2026Article
- Context matters for drug targeting.Nature chemical biology · 2026Article
- Mitochondrial Metabolic Reprogramming in Glioma: Mechanisms of Tumorigenesis and Implications for Clinical Therapy.CNS neuroscience & therapeutics · 2026Review
- Article
- Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.Cell · 2026Article
- Vorasidenib improves response to subsequent chemoradiation in a genetically engineered mouse model of IDH-mutant glioma.Science translational medicine · 2026Article
- Dynamic control of nucleotide metabolism in physiology and disease.Nature cell biology · 2026Review
- DHODH-Mediated Suppression of Ferroptosis Supports Radioresistance and Represents a Therapeutic Vulnerability in Lung Cancer.Cancer research · 2026Article
- Mitochondria transfer in glioblastoma.Neuro-oncology · 2026Review
- Murine modeling of IDH-mutant 1p/19q-codeleted oligodendroglioma reveals genotype specific phenotypes.bioRxiv : the preprint server for biology · 2026Article
- Current and emerging therapies in IDH-mutant glioma.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Brain cells refine nitrogen choice with maturity.Nature metabolism · 2026Article
- Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.Nature metabolism · 2026Article
- DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance.Cell death & disease · 2026Article
- Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment.Molecular cancer · 2026Review
- The oncogenic control of nucleotide synthesis.Oncogenesis · 2026Review
- Succinate dehydrogenase-deficient cancer cells have increased susceptibility to Ym155-induced DNA damage.Endocrine-related cancer · 2026Article
- Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer.Nature communications · 2026Article
- Targeting Metabolic Vulnerabilities in Glioblastoma: a Framework for Multi-node Combination Therapy.Current oncology reports · 2026Review
- Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.Neuro-oncology · 2026Article
31 more citing papers are in PubMed but not listed here.
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Authors and funding
51 authors at 16 institutions in 4 countries.
Diana D ShiDepartment of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA 02215, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Milan R SavaniChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Michael M LevittChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Adam C WangDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Jennifer E EndressLudwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Cylaina E BirdDepartment of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Joseph BuehlerChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sylwia A StopkaDepartment of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Michael S ReganDepartment of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Yu-Fen LinDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Vinesh T PuliyappadambaChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Wenhua GaoDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Januka KhanalDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Laura EvansBayer HealthCare Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
Joyce H LeeDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Lei GuoQuantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yi XiaoChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Min XuChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Bofu HuangDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Rebecca B JenningsDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Dennis M BonalLurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
Misty S Martin-SandovalChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Tammie DangDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Lauren C GattieChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Amy B CameronLurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
Sungwoo LeeNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
John M AsaraDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Harley I KornblumDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Behavioral Sciences, and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90024, USA.
Tak W MakThe Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON M5G 2M9, Canada; The Princess Margaret Cancer Centre and Ontario Cancer Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Ryan E LooperDepartment of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Quang-De NguyenLurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
Sabina SignorettiDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Stefan GradlBayer AG, Muellerstrasse 178, 13353 Berlin, Germany.
Andreas SutterBayer AG, Muellerstrasse 178, 13353 Berlin, Germany.
Michael JeffersBayer HealthCare Pharmaceuticals, Inc., Whippany, NJ 07981, USA.
Andreas JanzerBayer AG, Muellerstrasse 178, 13353 Berlin, Germany.
Mark A LehrmanDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Lauren G ZachariasChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Thomas P MathewsChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Julie-Aurore LosmanDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Timothy E RichardsonDepartment of Pathology, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Daniel P CahillDepartment of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Ralph J DeBerardinisChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Keith L LigonDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Children's Hospital Boston, Boston, MA 02115, USA.
Lin XuQuantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Peter LyDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Nathalie Y R AgarDepartment of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Kalil G AbdullahDepartment of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Hillman Comprehensive Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
Isaac S HarrisWilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
William G KaelinDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.
Samuel K McBrayerChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA. Electronic address: samuel.mcbrayer@utsouthwestern.edu.
Brigham and Women's Hospital · USChildren's Medical Center · USThe University of Texas Southwestern Medical Center · USBayer (Germany) · DEDana-Farber Cancer Institute · USBayer (United States) · USHarvard University · USBeth Israel Deaconess Medical Center · USDaegu-Gyeongbuk Medical Innovation Foundation · KRNeurological Surgery · USOntario Institute for Cancer Research · CAThe University of Texas Health Science Center at San Antonio · USUniversity of California, Los Angeles · USUniversity of Pittsburgh · USUniversity of Rochester Medical Center · USUniversity of Utah · US
Funding
VectorP30CA006516 · NCI · DANA-FARBER CANCER INSTITUTE · PI Irene M. Ghobrial · 1985 to 2026
$330.6MTreating the P13-Kinase/AKTP50CA101942 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI David McDermott · 2003 to 2026
$53.4MMedical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MTuberous Sclerosis-Pathway and PathogenesisP01CA120964 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI David J. Kwiatkowski · 2007 to 2026
$35.9MTargeting the Vasular SystemP50CA165962 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Tracy T Batchelor · 2013 to 2026
$33.5MUCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Yvonne Yu-Hsuan Chen · 2017 to 2026
$25.2MThe von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer: Insights into Oxygen Sensing and Treating Cancers Caused by Undruggable MutationsR35CA210068 · NCI · DANA-FARBER CANCER INST · PI WILLIAM G. KAELIN · 2016 to 2026
$10.8MTRD 3 - Enabling Technologies for Intraprocedural GuidanceP41EB028741 · NIBIB · BRIGHAM AND WOMEN'S HOSPITAL · PI Oliver Jonas · 2021 to 2026
$10.7MTrans Network ProjectU54CA210180 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI SARKARIA, JANN N., WHITE, FOREST M · 2016 to 2020
$10.2MUCLA IDDRC: Translational CoreP50HD103557 · NICHD · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Peyman Golshani, SUMA JACOB · 2020 to 2026
$9.6MMetabolic Regulators of Tumor Growth and ProgressionR35CA220449 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI RALPH J DEBERARDINIS · 2017 to 2026
$9.4MUT Southwestern NORCP30DK127984 · NIDDK · UT SOUTHWESTERN MEDICAL CENTER · PI Jeffrey M Zigman · 2022 to 2026
$7.4MNCI NIH HHS F30 CA183474NCI NIH HHS F30 CA271634NCI NIH HHS K22 CA237752NCI NIH HHS P01 CA120964NCI NIH HHS P30 CA006516NCI NIH HHS P50 CA101942NCI NIH HHS P50 CA165962NCI NIH HHS P50 CA211015NCI NIH HHS R01 CA188652NCI NIH HHS R01 CA258586NCI NIH HHS R35 CA210068NCI NIH HHS R35 CA220449NCI NIH HHS U19 CA264504NCI NIH HHS U54 CA210180NIBIB NIH HHS P41 EB028741NIBIB NIH HHS T32 EB025823NIDDK NIH HHS P30 DK127984NIGMS NIH HHS T32 GM007753
Abstract
Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
Indexed as
Brain NeoplasmsGliomaLeukemiaAnimalsEnzyme InhibitorsIsocitrate DehydrogenaseMiceMutationPyrimidinesSalicylanilidesTriazolesEnzyme InhibitorsIsocitrate DehydrogenaseorludodstatPyrimidinesSalicylanilidesTriazolescancer metabolismDHODHgenetically engineered mouse modelgliomaIDHisocitrate dehydrogenasepyrimidine nucleotides
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