Articles producció científica> Enginyeria Electrònica, Elèctrica i Automàtica

BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy

  • Identification data

    Identifier: imarina:9286900
    Authors:
    McGrail, KimberleyGranado-Martinez, PaulaEsteve-Puig, RosauraGarcia-Ortega, SaraDing, YuxinSanchez-Redondo, SaraFerrer, BertaHernandez-Losa, JavierCanals, FrancescManzano, AnnaNavarro-Sabate, AuraBartrons, RamonYanes, OscarPerez-Alea, MileidysMunoz-Couselo, EvaGarcia-Patos, VicencRecio, Juan A
    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).
  • Others:

    Author, as appears in the article.: McGrail, Kimberley; Granado-Martinez, Paula; Esteve-Puig, Rosaura; Garcia-Ortega, Sara; Ding, Yuxin; Sanchez-Redondo, Sara; Ferrer, Berta; Hernandez-Losa, Javier; Canals, Francesc; Manzano, Anna; Navarro-Sabate, Aura; Bartrons, Ramon; Yanes, Oscar; Perez-Alea, Mileidys; Munoz-Couselo, Eva; Garcia-Patos, Vicenc; Recio, Juan A
    Department: Enginyeria Electrònica, Elèctrica i Automàtica
    URV's Author/s: Yanes Torrado, Óscar
    Keywords: Stress, physiological Sorafenib Proto-oncogene proteins b-raf Phosphofructokinase-2 Pfkfb2 protein, human Nras protein, human Mutation Mutant melanoma Membrane proteins Melanoma Humans Gtp phosphohydrolases Glycolysis Glucose Cell line, tumor Braf protein, human 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: 2024-10-12
    Papper version: info:eu-repo/semantics/publishedVersion
    Link to the original source: https://www.nature.com/articles/s41467-022-34907-0
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Papper original source: Nature Communications. 13 (1): 7113-7113
    APA: McGrail, Kimberley; Granado-Martinez, Paula; Esteve-Puig, Rosaura; Garcia-Ortega, Sara; Ding, Yuxin; Sanchez-Redondo, Sara; Ferrer, Berta; Hernandez-L (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
    Article's DOI: 10.1038/s41467-022-34907-0
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2022
    Publication Type: Journal Publications
  • Keywords:

    Biochemistry, Genetics and Molecular Biology (Miscellaneous),Chemistry (Miscellaneous),Multidisciplinary Sciences,Physics and Astronomy (Miscellaneous)
    Stress, physiological
    Sorafenib
    Proto-oncogene proteins b-raf
    Phosphofructokinase-2
    Pfkfb2 protein, human
    Nras protein, human
    Mutation
    Mutant melanoma
    Membrane proteins
    Melanoma
    Humans
    Gtp phosphohydrolases
    Glycolysis
    Glucose
    Cell line, tumor
    Braf protein, human
    tumors
    survival
    raf
    phosphorylation
    mutations
    kinase
    glucose
    cancer
    6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
    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
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