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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Imidazoles / pharmacology
  • MCF-7 Cells
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mice
  • Mice, SCID
  • Molecular Docking Simulation
  • Mutation
  • Oximes / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Receptors, Aryl Hydrocarbon / antagonists & inhibitors
  • Receptors, Aryl Hydrocarbon / genetics*
  • Resveratrol / pharmacology
  • Resveratrol / therapeutic use
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Transcription Factors
  • Tumor Burden / drug effects
  • Vemurafenib / therapeutic use
  • Xenograft Model Antitumor Assays


  • Enzyme Inhibitors
  • Imidazoles
  • Oximes
  • Protein Kinase Inhibitors
  • Receptors, Aryl Hydrocarbon
  • Transcription Factors
  • Vemurafenib
  • Proto-Oncogene Proteins B-raf
  • Resveratrol
  • dabrafenib