Oncotarget

Research Papers:

Mitochondrial oxidative stress is the achille’s heel of melanoma cells resistant to Braf-mutant inhibitor

Paola Corazao-Rozas, Pierre Guerreschi, Manel Jendoubi, Fanny André, Aurélie Jonneaux, Camille Scalbert, Guillaume Garçon, Myriam Mallet-Martino, Stéphane Balayssac, Stephane Rocchi, Ariel Savina, Pierre Formstecher, Laurent Mortier, Jerome Kluza and Philippe Marchetti _

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Oncotarget. 2013; 4:1986-1998. https://doi.org/10.18632/oncotarget.1420

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Abstract

Paola Corazao-Rozas1,*, Pierre Guerreschi1,*, Manel Jendoubi1,*, Fanny André1, Aurélie Jonneaux1, Camille Scalbert1, Guillaume Garçon2, Myriam Malet-Martino3, Stéphane Balayssac3, Stephane Rocchi4, Ariel Savina5, Pierre Formstecher1, Laurent Mortier1, Jérome Kluza1, and Philippe Marchetti1,6

1 Unit 837 Equipe 4 Inserm and Faculté de Médecine, Université de Lille II 1 Place Verdun 59045 Cedex, France

2 EA 4483 Faculté des Sciences Pharmaceutiques et Biologiques de Lille 3, rue du Professeur Laguesse BP83 59006 Lille Cedex

3 Laboratoire SPCMIB, UMR CNRS 5068 Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France

4 INSERM U1065, Centre Méditerranéen de Médecine Moléculaire 151 route Saint-Antoine de Ginestière 06204 Nice cedex 3

5 Roche SAS 30 cours de l’ile Seguin 92650 Boulogne Billancourt Cedex

6 Centre de Bio-Pathologie, Plate-forme de Biothérapie, Banque de Tissus, CHRU Lille, France

* PC-R, PG and MJ contribute equally to this work

JK and PM share co-seniorship of this paper

Correspondence:

Philippe Marchetti, email:

Keywords: metabolism, oxidative phosphorylation, elesclomol, ROS

Received: September 17, 2013 Accepted: October 4, 2013 Published: October 6, 2013

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.


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