Author, as appears in the article.: McGrail K; Granado-Martínez P; Esteve-Puig R; García-Ortega S; Ding Y; Sánchez-Redondo S; Ferrer B; Hernandez-Losa J; Canals F; Manzano A; Navarro-Sabaté A; Bartrons R; Yanes O; Pérez-Alea M; Muñoz-Couselo E; Garcia-Patos V; Recio JA

Department: Enginyeria Electrònica, Elèctrica i Automàtica

URV's Author/s: Yanes Torrado, Óscar

Keywords: Mutant melanoma tumors survival raf phosphorylation mutations kinase glucose cancer 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase

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.© 2022. The Author(s).

Thematic Areas: Zootecnia / recursos pesqueiros Saúde coletiva Química Psicología Planejamento urbano e regional / demografia Physics and astronomy (miscellaneous) Physics and astronomy (all) Odontología Nutrição Multidisciplinary sciences Multidisciplinary Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Matemática / probabilidade e estatística Interdisciplinar Geociências General physics and astronomy General medicine General chemistry General biochemistry,genetics and molecular biology Farmacia Engenharias iv Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência da computação Chemistry (miscellaneous) Chemistry (all) Biotecnología Biodiversidade Biochemistry, genetics and molecular biology (miscellaneous) Biochemistry, genetics and molecular biology (all) Astronomia / física Antropologia / arqueologia

licence for use: https://creativecommons.org/licenses/by/3.0/es/

Author's mail: oscar.yanes@urv.cat

Author identifier: 0000-0003-3695-7157

Record's date: 2023-02-19

Papper version: info:eu-repo/semantics/publishedVersion

Link to the original source: https://www.nature.com/articles/s41467-022-34907-0

Papper original source: Nature Communications. 13 (1): 7113-7113

APA: McGrail K; Granado-Martínez P; Esteve-Puig R; García-Ortega S; Ding Y; Sánchez-Redondo S; Ferrer B; Hernandez-Losa J; Canals F; Manzano A; Navarro-Sab (2022). BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy. Nature Communications, 13(1), 7113-7113. DOI: 10.1038/s41467-022-34907-0

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Article's DOI: 10.1038/s41467-022-34907-0

Entity: Universitat Rovira i Virgili

Journal publication year: 2022

Publication Type: Journal Publications