2026-04-17T07:57:59Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1918042025-12-05T09:21:06Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917

urn:hdl:2445/191804 BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy 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. Melanoma Estrès (Fisiologia) Melanoma Stress (Physiology) 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. 2022-12-23T08:24:48Z 2022-12-23T08:24:48Z 2022-11-19 2022-12-19T11:26:53Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1038/s41467-022-34907-0 Nature Communications, 2022, vol. 13, issue. 1 https://doi.org/10.1038/s41467-022-34907-0 cc by (c) Mcgrail, Kimberley et al., 2022 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Springer Science and Business Media LLC Articles publicats en revistes (Ciències Fisiològiques)