2. Academic Validation
  3. 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. [email protected].
  • 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. [email protected].
  • 11 IGDR (Institut de Génétique et Développement de Rennes)-UMR6290, CNRS, Univ Rennes, F-35000, Rennes, France. [email protected].
  • 12 Department of Molecular Genetics and Genomics, Hospital University of Rennes (CHU Rennes), F-35000, Rennes, France. [email protected].
PMID: 30429474 DOI: 10.1038/s41467-018-06951-2
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18997
    98.94%, BRAF Inhibitor
    Raf
  • HY-18972
    99.94%, BRAF Inhibitor