Mcgrail, KimberleyGranado Martínez, PaulaEsteve Puig, RosauraGarcía Ortega, SaraDing, YuxinSánchez Redondo, SaraFerrer, BertaHernandez Losa, JavierCanals, FrancescManzano Cuesta, AnnaNavarro i Sabaté, ÀureaBartrons Bach, RamonYanes, OscarPérez Alea, MileidysMuñoz Couselo, EvaGarcía-Patos Briones, VicenteRecio, Juan A.2022-12-232022-12-232022-11-192041-1723https://hdl.handle.net/2445/191804NRAS-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.22 p.application/pdfengcc by (c) Mcgrail, Kimberley et al., 2022http://creativecommons.org/licenses/by/3.0/es/MelanomaEstrès (Fisiologia)MelanomaStress (Physiology)info:eu-repo/semantics/article7282432022-12-19info:eu-repo/semantics/openAccess36402789