DDRE-22. TARGETING SERINE SYNTHESIS IN BRAIN METASTASIS
| Autor: | Samuel F. Bakhoum, Rakesh K. Jain, Matija Snuderl, Vinagolu K. Rajasekhar, Ariana Plasger, Victoria Osorio-Vasquez, Michael Davies, Gino B. Ferraro, Roozbeh Eskandari, Sophia Bustraan, Lewis C. Cantley, Michael E. Pacold, Ahmed Ali, Bryan Ngo, Eugenie Kim, Grant M. Fischer, Shawn M. Davidson, Paolo Cotzia, Min Yu, Sophia Doll, Matthew G. Vander Heiden, Sarah Bacha, David M. Sabatini, Eva Hernando, Edward R. Kastenhuber, Roger Liang, Roshan K. Sriram, John H. Healey, Drew R. Jones, Alba Luengo, Kayvan R. Keshari, Matthias Mann, Jean J. Zhao |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Chemistry business.industry Metabolic Drug Targets Resistance medicine.disease Small molecule Supplement Abstracts Amino acid Serine Text mining Biochemistry Oxidoreductase Glycine medicine AcademicSubjects/MED00300 AcademicSubjects/MED00310 Nucleotide business Brain metastasis |
| Zdroj: | Neuro-oncology Advances |
| ISSN: | 2632-2498 |
| DOI: | 10.1093/noajnl/vdab024.044 |
| Popis: | The brain environment is low in amino acids, including serine and glycine, both of which are important for tumor growth as they are precursors of proteins and nucleotide bases. How tumor cells overcome these conditions to proliferate and survive in the brain is incompletely understood. Here, we show that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first and rate-limiting step of glucose-derived serine synthesis, enables brain metastasis in multiple human types and in preclinical models. Genetic suppression and small molecule inhibition of PHGDH attenuated brain metastasis, but not extra cranial tumors, and improved the overall survival of mice bearing brain metastasis. These results demonstrate that the tumor nutrient microenvironment determines tumor cell sensitivity to loss of serine synthesis pathway activity and raise the possibility that serine synthesis inhibitors may be useful in the treatment of brain metastases. |
| Databáze: | OpenAIRE |
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