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

Author

Listed:
  • 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
    MAJ3 Capital S.L)

  • 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
    Spanish National Cancer Research Centre (CNIO))

  • Berta Ferrer

    (Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
    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
    Instituto de Salud Carlos III)

  • Mileidys Pérez-Alea

    (Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
    Advance Biodesign)

  • Eva Muñoz-Couselo

    (Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
    Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Hospital Barcelona-UAB)

  • Vicenç Garcia-Patos

    (Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB
    Vall d’Hebron Hospital Barcelona-UAB)

  • Juan A. Recio

    (Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Hospital Barcelona-UAB)

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.

Suggested Citation

  • 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, 2022. "BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34907-0
    DOI: 10.1038/s41467-022-34907-0
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    References listed on IDEAS

    as
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