Repositori URV

Identificador: imarina:9286900

Handle: https://hdl.handle.net/20.500.11797/imarina9286900

Autores:
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

Resumen:
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).