De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma.

Animals Brain Neoplasms / drug therapy Enzyme Inhibitors / therapeutic use Glioma / drug therapy Isocitrate Dehydrogenase / genetics Leukemia Mice Mutation Pyrimidines / pharmacology Salicylanilides Triazoles
DHODH IDH cancer metabolism genetically engineered mouse model glioma isocitrate dehydrogenase pyrimidine nucleotides

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
12 09 2022
Historique:
received: 30 11 2021
revised: 09 06 2022
accepted: 26 07 2022
pubmed: 20 8 2022
medline: 16 9 2022
entrez: 19 8 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ccell.2022.07.011 PMID: 35985343 PMC: PMC9515386
pubmed: 35985343
pii: S1535-6108(22)00324-5
doi: 10.1016/j.ccell.2022.07.011
pmc: PMC9515386
mid: NIHMS1828337
pii:
doi:

Substances chimiques

Enzyme Inhibitors 0
Pyrimidines 0
Salicylanilides 0
Triazoles 0
Isocitrate Dehydrogenase EC 1.1.1.41
orludodstat X8GF945GMK

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

939-956.e16

Subventions

Organisme : NCI NIH HHS
ID : F30 CA183474
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA271634
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220449
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188652
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA211015
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258586
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA165962
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA210180
Pays : United States
Organisme : NIBIB NIH HHS
ID : T32 EB025823
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA264504
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103557
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA101942
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA237752
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA120964
Pays : United States
Organisme : NIBIB NIH HHS
ID : P41 EB028741
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210068
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests R.J.D., W.G.K., and S.K.M. have served as paid advisors to Agios Pharmaceuticals. W.G.K. receives compensation for roles as an Eli Lilly and LifeMine Therapeutics Board Director, a founder of Tango Therapeutics and Cedilla Therapeutics, and a scientific advisor for Fibrogen, IconOVir Bio, Circle Pharma, Nextext Invest, and Casdin Capital. K.L.L. receives research support from Eli Lilly and Company via the DFCI. S.K.M. and W.G.K. received research funding from Bayer Pharmaceuticals. Bayer had no influence over the design, execution, or interpretation of studies. N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. S.G., A.S., M.S., A.J., and L.E. are employees at Bayer. S.G., A.S., and A.J. hold stock in Bayer. D.P.C. has consulted for Lilly, GlaxoSmithKline, and Boston Pharmaceuticals and serves on the advisory board of Pyramid Biosciences, which includes an equity interest. All other authors declare no competing interests.

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Auteurs

Diana D Shi (DD)

Department 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 Savani (MR)

Children'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 Levitt (MM)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Adam C Wang (AC)

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Jennifer E Endress (JE)

Ludwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.

Cylaina E Bird (CE)

Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.

Joseph Buehler (J)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Sylwia A Stopka (SA)

Department 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 Regan (MS)

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Yu-Fen Lin (YF)

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Vinesh T Puliyappadamba (VT)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Wenhua Gao (W)

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Januka Khanal (J)

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Laura Evans (L)

Bayer HealthCare Pharmaceuticals, Inc., Cambridge, MA 02142, USA.

Joyce H Lee (JH)

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Lei Guo (L)

Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Yi Xiao (Y)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Min Xu (M)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Bofu Huang (B)

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Rebecca B Jennings (RB)

Department 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 Bonal (DM)

Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.

Misty S Martin-Sandoval (MS)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Tammie Dang (T)

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Lauren C Gattie (LC)

Children'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 Cameron (AB)

Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.

Sungwoo Lee (S)

New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.

John M Asara (JM)

Department 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 Kornblum (HI)

Department 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 Mak (TW)

The 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 Looper (RE)

Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

Quang-De Nguyen (QD)

Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.

Sabina Signoretti (S)

Department 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 Gradl (S)

Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany.

Andreas Sutter (A)

Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany.

Michael Jeffers (M)

Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ 07981, USA.

Andreas Janzer (A)

Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany.

Mark A Lehrman (MA)

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Lauren G Zacharias (LG)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Thomas P Mathews (TP)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Julie-Aurore Losman (JA)

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Timothy E Richardson (TE)

Department of Pathology, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX 78229, USA.

Daniel P Cahill (DP)

Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Ralph J DeBerardinis (RJ)

Children'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 Ligon (KL)

Department 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 Xu (L)

Quantitative 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 Ly (P)

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Nathalie Y R Agar (NYR)

Department 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 Abdullah (KG)

Department 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 Harris (IS)

Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.

William G Kaelin (WG)

Department 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 McBrayer (SK)

Children'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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › Isocitrate dehydrogenases › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Leucémies › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Composés chimiques organiques › Amines › Dérivés de l'aniline › Anilides › Salicylanilides › De novo pyrimidine synthesis is a targetable...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Triazoles › De novo pyrimidine synthesis is a targetable...