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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.<\/jats:p>","DOI":"10.3390\/ijms26178241","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:26:31Z","timestamp":1756189591000},"page":"8241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy"],"prefix":"10.3390","volume":"26","author":[{"given":"Laura","family":"Soumoy","sequence":"first","affiliation":[{"name":"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"},{"name":"INSERM U981, Gustave Roussy Cancer Campus, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2312-567X","authenticated-orcid":false,"given":"Aline","family":"Genbauffe","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorianne","family":"Sant\u2019Angelo","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maude","family":"Everaert","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a","family":"Mukeba-Harchies","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6704-2032","authenticated-orcid":false,"given":"Jean-Emmanuel","family":"Sarry","sequence":"additional","affiliation":[{"name":"Centre de Recherches en Canc\u00e9rologie de Toulouse, Universit\u00e9 de Toulouse, Inserm, CNRS, 31100 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0838-2432","authenticated-orcid":false,"given":"Anne-Emilie","family":"Decl\u00e8ves","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5051-231X","authenticated-orcid":false,"given":"Fabrice","family":"Journe","sequence":"additional","affiliation":[{"name":"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"},{"name":"Laboratory of Clinical and Experimental Oncology, Institut Jules Bordet, Universit\u00e9 Libre de Bruxelles, 1000 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1016\/j.cell.2015.05.044","article-title":"Genomic Classification of Cutaneous Melanoma","volume":"161","author":"Akbani","year":"2015","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.bbagen.2018.01.018","article-title":"Melanoma metabolism contributes to the cellular responses to MAPK\/ERK pathway inhibitors","volume":"1862","author":"Marchetti","year":"2018","journal-title":"Biochim. 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