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, Javier Hernandez-Losa, Francesc Canals, Anna Manzano, Aura Navarro-Sabaté, Ramón Bartrons, Oscar Yanes, Mileidys Pérez-Alea, Eva Muñoz-Couselo, Vicenç Garcia-Patos and Juan A. Recio ()
Additional contact information
Kimberley McGrail: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Paula Granado-Martínez: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Rosaura Esteve-Puig: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Sara García-Ortega: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Yuxin Ding: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Sara Sánchez-Redondo: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Berta Ferrer: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Javier Hernandez-Losa: Vall d’Hebron Hospital Barcelona-UAB
Francesc Canals: Vall d’Hebron Institute of Oncology (VHIO)
Anna Manzano: University of Barcelona, Bellvitge Biomedical Research Institute
Aura Navarro-Sabaté: University of Barcelona, Bellvitge Biomedical Research Institute
Ramón Bartrons: University of Barcelona, Bellvitge Biomedical Research Institute
Oscar Yanes: Universitat Rovira i Virgili, Department of Electronic Engineering, IISPV
Mileidys Pérez-Alea: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Eva Muñoz-Couselo: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Vicenç Garcia-Patos: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
Juan A. Recio: Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB

Nature Communications, 2022, vol. 13, issue 1, 1-22

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 NRASQ61-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 NRASQ61 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 NRASQ61-mutated melanoma combining metabolic stress (glycolysis inhibitors) and previously approved drugs, such as sorafenib.

Date: 2022
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DOI: 10.1038/s41467-022-34907-0

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