1. Academic Validation
  2. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma

Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma

  • Nat Commun. 2018 Nov 14;9(1):4775. doi: 10.1038/s41467-018-06951-2.
Sébastien Corre 1 Nina Tardif 2 Nicolas Mouchet 2 Héloïse M Leclair 2 Lise Boussemart 2 3 Arthur Gautron 2 Laura Bachelot 2 Anthony Perrot 2 Anatoly Soshilov 4 Aljosja Rogiers 5 6 Florian Rambow 5 6 Erwan Dumontet 7 Karin Tarte 7 Alban Bessede 8 Gilles J Guillemin 9 Jean-Christophe Marine 5 6 Michael S Denison 4 David Gilot 10 Marie-Dominique Galibert 11 12
Affiliations

Affiliations

  • 1 IGDR (Institut de Génétique et Développement de Rennes)-UMR6290, CNRS, Univ Rennes, F-35000, Rennes, France. sebastien.corre@univ-rennes1.fr.
  • 2 IGDR (Institut de Génétique et Développement de Rennes)-UMR6290, CNRS, Univ Rennes, F-35000, Rennes, France.
  • 3 Department of Dermatology, Hospital University of Rennes (CHU Rennes), F-35000, Rennes, France.
  • 4 Department of Environmental Toxicology, University of California, Meyer Hall, Davis, CA, 95616, USA.
  • 5 Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, Leuven, 3000, Belgium.
  • 6 Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, 3000, Belgium.
  • 7 MICMAC (MIcroenvironment, Cell differentiation, iMmunology And Cancer)-UMR_S 1236, Inserm, Univ Rennes, F-35000, Rennes, France.
  • 8 ImmuSmol, Pessac, F-33600, France.
  • 9 Neuroinflammation Group, MND and Neurodegenerative Diseases Research Center, Macquarie University, Sydney, NSW, 2109, Australia.
  • 10 IGDR (Institut de Génétique et Développement de Rennes)-UMR6290, CNRS, Univ Rennes, F-35000, Rennes, France. david.gilot@univ-rennes1.fr.
  • 11 IGDR (Institut de Génétique et Développement de Rennes)-UMR6290, CNRS, Univ Rennes, F-35000, Rennes, France. mgaliber@univ-rennes1.fr.
  • 12 Department of Molecular Genetics and Genomics, Hospital University of Rennes (CHU Rennes), F-35000, Rennes, France. mgaliber@univ-rennes1.fr.
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.

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