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http://hdl.handle.net/2445/191804
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DC Field | Value | Language |
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dc.contributor.author | Mcgrail, Kimberley | - |
dc.contributor.author | Granado Martínez, Paula | - |
dc.contributor.author | Esteve Puig, Rosaura | - |
dc.contributor.author | García Ortega, Sara | - |
dc.contributor.author | Ding, Yuxin | - |
dc.contributor.author | Sánchez Redondo, Sara | - |
dc.contributor.author | Ferrer, Berta | - |
dc.contributor.author | Hernandez Losa, Javier | - |
dc.contributor.author | Canals, Francesc | - |
dc.contributor.author | Manzano Cuesta, Anna | - |
dc.contributor.author | Navarro Sabaté, Aura | - |
dc.contributor.author | Bartrons Bach, Ramon | - |
dc.contributor.author | Yanes, Oscar | - |
dc.contributor.author | Pérez Alea, Mileidys | - |
dc.contributor.author | Muñoz Couselo, Eva | - |
dc.contributor.author | García-Patos Briones, Vicente | - |
dc.contributor.author | Recio, Juan A. | - |
dc.date.accessioned | 2022-12-23T08:24:48Z | - |
dc.date.available | 2022-12-23T08:24:48Z | - |
dc.date.issued | 2022-11-19 | - |
dc.identifier.issn | 2041-1723 | - |
dc.identifier.uri | http://hdl.handle.net/2445/191804 | - |
dc.description.abstract | NRAS-mutated melanoma lacks a specific line of treatment. Metabolic reprogramming is considered a novel target to control cancer; however, NRAS-oncogene contribution to this cancer hallmark is mostly unknown. Here, we show that NRAS(Q61)-mutated melanomas specific metabolic settings mediate cell sensitivity to sorafenib upon metabolic stress. Mechanistically, these cells are dependent on glucose metabolism, in which glucose deprivation promotes a switch from CRAF to BRAF signaling. This scenario contributes to cell survival and sustains glucose metabolism through BRAF-mediated phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2/3 (PFKFB2/PFKFB3). In turn, this favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop that couples glycolytic flux and the RAS signaling pathway. An in vivo treatment of NRAS(Q61) mutant melanomas, including patient-derived xenografts, with 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence for NRAS-oncogene contributions to metabolic rewiring and a proof-of-principle for the treatment of NRAS(Q61)-mutated melanoma combining metabolic stress (glycolysis inhibitors) and previously approved drugs, such as sorafenib. Targeted therapeutic options for NRAS-mutant melanoma are limited. Here, the authors show that under metabolic stress NRAS-mutant melanoma cells activate a BRAF-dependent glycolysis pathway for survival, leading to improve efficacy of sorafenib when combined with glycolysis inhibitors. | - |
dc.format.extent | 22 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Springer Science and Business Media LLC | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1038/s41467-022-34907-0 | - |
dc.relation.ispartof | Nature Communications, 2022, vol. 13, issue. 1 | - |
dc.relation.uri | https://doi.org/10.1038/s41467-022-34907-0 | - |
dc.rights | cc by (c) Mcgrail, Kimberley et al., 2022 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Ciències Fisiològiques) | - |
dc.subject.classification | Melanoma | - |
dc.subject.classification | Estrès (Fisiologia) | - |
dc.subject.other | Melanoma | - |
dc.subject.other | Stress (Physiology) | - |
dc.title | BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 728243 | - |
dc.date.updated | 2022-12-19T11:26:53Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 36402789 | - |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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File | Description | Size | Format | |
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s41467-022-34907-0.pdf | 9.26 MB | Adobe PDF | View/Open |
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