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De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma.
Shi, Diana D; Savani, Milan R; Levitt, Michael M; Wang, Adam C; Endress, Jennifer E; Bird, Cylaina E; Buehler, Joseph; Stopka, Sylwia A; Regan, Michael S; Lin, Yu-Fen; Puliyappadamba, Vinesh T; Gao, Wenhua; Khanal, Januka; Evans, Laura; Lee, Joyce H; Guo, Lei; Xiao, Yi; Xu, Min; Huang, Bofu; Jennings, Rebecca B; Bonal, Dennis M; Martin-Sandoval, Misty S; Dang, Tammie; Gattie, Lauren C; Cameron, Amy B; Lee, Sungwoo; Asara, John M; Kornblum, Harley I; Mak, Tak W; Looper, Ryan E; Nguyen, Quang-De; Signoretti, Sabina; Gradl, Stefan; Sutter, Andreas; Jeffers, Michael; Janzer, Andreas; Lehrman, Mark A; Zacharias, Lauren G; Mathews, Thomas P; Losman, Julie-Aurore; Richardson, Timothy E; Cahill, Daniel P; DeBerardinis, Ralph J; Ligon, Keith L; Xu, Lin; Ly, Peter; Agar, Nathalie Y R; Abdullah, Kalil G; Harris, Isaac S; Kaelin, William G.
Afiliação
  • 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.
  • 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.
  • Levitt MM; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Wang AC; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Endress JE; Ludwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
  • Bird CE; Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
  • Buehler J; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 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.
  • Regan MS; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Lin YF; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Puliyappadamba VT; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Gao W; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Khanal J; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Evans L; Bayer HealthCare Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
  • Lee JH; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Guo L; Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Xiao Y; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Xu M; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Huang B; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 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.
  • Bonal DM; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • Martin-Sandoval MS; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Dang T; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 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.
  • Cameron AB; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • Lee S; New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
  • 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.
  • 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.
  • 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
  • Looper RE; Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
  • Nguyen QD; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
  • 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.
  • Gradl S; Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany.
  • Sutter A; Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany.
  • Jeffers M; Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ 07981, USA.
  • Janzer A; Bayer AG, Muellerstrasse 178, 13353 Berlin, Germany.
  • Lehrman MA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zacharias LG; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Mathews TP; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Losman JA; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 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.
  • Cahill DP; Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 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 Compr
  • 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.
  • 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.
  • Ly P; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 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, M
  • 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.
  • Harris IS; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 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.
Cancer Cell ; 40(9): 939-956.e16, 2022 09 12.
Article em En | MEDLINE | ID: mdl-35985343
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Leucemia / Glioma Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Leucemia / Glioma Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article