BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy
Kimberley McGrail, Paula Granado‐Martínez, Rosaura Esteve‐Puig, Sara García-Ortega, Yuxin Ding, Sara Sánchez‐Redondo, Berta Ferrer-Rosell, Javier Hernández‐Losa, Françesc Canals, Ànna Manzano, Àurea Navarro‐Sabaté, Ramón Bartrons, Óscar Yanes, Mileidys Pérez‐Alea, Eva Muñoz‐Couselo, Vicenç García-Patos, Juan A. Recio
Abstract
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.