title: Mitochondrial oxidative stress is the Achille's heel of melanoma cells resistant to Braf-mutant inhibitor.
abstract: Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition.
authors.affiliation: Unit 837 Equipe 4 Inserm and Faculté de Médecine, Université de Lille II 1 Place Verdun 59045 Cedex, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Corazao-Rozas
authors.forename: Pierre
authors.initials: P
authors.lastname: Guerreschi
authors.forename: Manel
authors.initials: M
authors.lastname: Jendoubi
authors.forename: Fanny
authors.initials: F
authors.lastname: André
authors.forename: Aurélie
authors.initials: A
authors.lastname: Jonneaux
authors.forename: Camille
authors.initials: C
authors.lastname: Scalbert
authors.forename: Guillaume
authors.initials: G
authors.lastname: Garçon
authors.forename: Myriam
authors.initials: M
authors.lastname: Malet-Martino
authors.forename: Stéphane
authors.initials: S
authors.lastname: Balayssac
authors.forename: Stephane
authors.initials: S
authors.lastname: Rocchi
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.forename: Pierre
authors.initials: P
authors.lastname: Formstecher
authors.forename: Laurent
authors.initials: L
authors.lastname: Mortier
authors.forename: Jérome
authors.initials: J
authors.lastname: Kluza
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf