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

  • Author(s): 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
  • et al.
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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