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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/191804
BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy
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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.
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MCGRAIL, Kimberley, GRANADO MARTÍNEZ, Paula, ESTEVE PUIG, Rosaura, GARCÍA ORTEGA, Sara, DING, Yuxin, SÁNCHEZ REDONDO, Sara, FERRER, Berta, HERNANDEZ LOSA, Javier, CANALS, Francesc, MANZANO CUESTA, Anna, NAVARRO I SABATÉ, Àurea, BARTRONS BACH, Ramon, YANES, Oscar, PÉREZ ALEA, Mileidys, MUÑOZ COUSELO, Eva, GARCÍA-PATOS BRIONES, Vicente, RECIO, Juan a.. BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy. _Nature Communications_. 2022. Vol. 13, núm. 1. [consulta: 25 de febrer de 2026]. ISSN: 2041-1723. [Disponible a: https://hdl.handle.net/2445/191804]