1. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma
- Author
-
Corre, Sébastien, Tardif, Nina, Mouchet, Nicolas, Leclair, Héloïse M., Boussemart, Lise, Gautron, Arthur, Bachelot, Laura, Perrot, Anthony, Soshilov, Anatoly, Rogiers, Aljosja, Rambow, Florian, Dumontet, Erwan, Tarte, Karin, Bessede, Alban, Guillemin, Gilles J., Marine, Jean-Christophe, Denison, Michael S., Gilot, David, Galibert, Marie-Dominique, Jonchère, Laurent, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], University of California [Davis] (UC Davis), University of California (UC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), VIB [Belgium], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Macquarie University, AVIESAN plan Cancer [ENV201308, ENV201603], Fondation ARC [PGA1*20160203868], Ligue National Contre le Cancer (LNCC) Departements du Grand-Ouest, Association 'Vaincre le Cancer', FHU CAMIn-CHU Rennes, Region Bretagne, University of Rennes 1, CNRS, Inserm, ministere de la Recherche, Ligue Contre le Cancer (Grand-Ouest), CNRS [UMR6290], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California, and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
- Subjects
Skin Neoplasms ,endocrine system diseases ,Drug Resistance ,Mice, SCID ,Mice ,Oximes ,Receptors ,2.1 Biological and endogenous factors ,Enzyme Inhibitors ,Aetiology ,lcsh:Science ,Melanoma ,Cancer ,Tumor ,Imidazoles ,respiratory system ,Tumor Burden ,Molecular Docking Simulation ,Aryl Hydrocarbon ,5.1 Pharmaceuticals ,MCF-7 Cells ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Development of treatments and therapeutic interventions ,Proto-Oncogene Proteins B-raf ,Science ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,SCID ,Article ,Cell Line ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,MD Multidisciplinary ,Genetics ,Animals ,Humans ,Protein Kinase Inhibitors ,neoplasms ,[SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology ,Xenograft Model Antitumor Assays ,Receptors, Aryl Hydrocarbon ,Vemurafenib ,Drug Resistance, Neoplasm ,Resveratrol ,Mutation ,Neoplasm ,lcsh:Q ,[SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology ,Transcription Factors - Abstract
BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance., Resistance to BRAF inhibitors limits their clinical benefit in melanoma patients. Here, the authors show that the Aryl hydrocarbon Receptor (AhR) is a key mediator of resistant genes and use resveratrol, an AhR antagonist, to revert resistance in melanoma bearing mice.
- Published
- 2018
- Full Text
- View/download PDF