title: Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells.
abstract: BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting.
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Franziska
authors.initials: F
authors.lastname: Baenke
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Chaneton
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Smith
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Niels
authors.initials: N
authors.lastname: Van Den Broek
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Hogan
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Haoran
authors.initials: H
authors.lastname: Tang
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Martin
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Galbraith
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Girotti
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dhomen
authors.affiliation: Cancer Metabolism Research Unit, Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK. Electronic address: e.gottlieb@beatson.gla.ac.uk.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.affiliation: Molecular Oncology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Electronic address: richard.marais@cruk.manchester.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005973:Glutamine / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D005973:Glutamine; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; Glutaminolysis; Melanoma; Metabolism; Resistance