[en] Targeted therapy with BRAFi has significantly improved outcomes for patients with BRAF-mutated metastatic melanoma. However, resistance mechanisms, particularly metabolic adaptations, such as increased glutaminolysis, present substantial clinical challenges. This study investigated the metabolic changes underlying BRAFi resistance in melanoma cells. Using pharmacological agents, including dabrafenib (BRAFi), pimasertib (MEKi), dasatinib (cKITi), and CB-839 (glutaminase inhibitor), we explored metabolic adaptations in melanoma cell lines harboring various mutations. Our methodologies included cell culture, qPCR, polysome profiling, animal studies in nude mice, and analyses of patient samples to evaluate the therapeutic potential of targeting glutaminolysis. Our findings confirmed that melanoma cells, with resistance to targeted therapies, exhibit metabolic adaptations, including enhanced glutaminolysis, increased mitochondrial content, and elevated antioxidative capacities. We evaluated the efficacy of CB-839 and demonstrated its ability to reduce the proliferation of resistant melanoma cells both in vitro and in vivo. Mechanistic studies revealed that CB-839 suppressed ATP production and TCA cycle intermediates in resistant cells while inducing oxidative stress in sensitive cells, thereby inhibiting their proliferation. High glutaminase expression in primary patient tumor samples was associated with poor prognosis. We identified a metabolic signature in tumors from patients responsive or unresponsive to BRAFi prior to treatment, which could serve as a predictive factor for BRAFi response. This study underscores the metabolic alterations driving resistance to BRAFi in melanoma cells and highlights the therapeutic potential of targeting glutaminolysis with CB-839. The identification of metabolic signatures in patient samples provides valuable insights for personalized treatment strategies, aiming to overcome resistance mechanisms and improve patient outcomes in melanoma management.
Disciplines :
Oncology
Author, co-author :
Soumoy, Laura; Laboratory of Human Anatomy & Experimental Oncology, Faculty of Medicine, Pharmacy and Biomedical Sciences, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium ; INSERM U981, Gustave Roussy Cancer Campus, 94800 Villejuif, France
Genbauffe, Aline ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory ; Laboratory of Human Anatomy & Experimental Oncology, Faculty of Medicine, Pharmacy and Biomedical Sciences, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium
Sant'Angelo, Dorianne; Laboratory of Human Anatomy & Experimental Oncology, Faculty of Medicine, Pharmacy and Biomedical Sciences, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium
Everaert, Maude; Laboratory of Human Anatomy & Experimental Oncology, Faculty of Medicine, Pharmacy and Biomedical Sciences, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium
Mukeba-Harchies, Léa; Laboratory of Human Anatomy & Experimental Oncology, Faculty of Medicine, Pharmacy and Biomedical Sciences, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium
Sarry, Jean-Emmanuel ; Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, CNRS, 31100 Toulouse, France
Declèves, Anne-Emilie ; Laboratory of Metabolic and Molecular Biochemistry, Faculty of Medicine, Pharmacy and Biomedical Sciences, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium
Journe, Fabrice ; Laboratory of Human Anatomy & Experimental Oncology, Faculty of Medicine, Pharmacy and Biomedical Sciences, Research Institute for Health Sciences and Technology, University of Mons, 7000 Mons, Belgium ; Laboratory of Clinical and Experimental Oncology, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium
Language :
English
Title :
Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.
Publication date :
25 August 2025
Journal title :
International Journal of Molecular Sciences
ISSN :
1661-6596
eISSN :
1422-0067
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
This work was supported by the University of Mons (2019-2022), the Health Institute of the University of Mons (2019-2022), the FRMH (2021), and \u201CLes Amis de l\u2019Institut Bordet\u201D (2021) from the Jules Bordet Institute (Brussels, Belgium).
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