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
  • 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.

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