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

Sébastien Corre (), Nina Tardif, Nicolas Mouchet, Héloïse M. Leclair, Lise Boussemart, Arthur Gautron, Laura Bachelot, Anthony Perrot, Anatoly Soshilov, Aljosja Rogiers, Florian Rambow, Erwan Dumontet, Karin Tarte, Alban Bessede, Gilles J. Guillemin, Jean-Christophe Marine, Michael S. Denison, David Gilot () and Marie-Dominique Galibert ()
Additional contact information
Sébastien Corre: Univ Rennes
Nina Tardif: Univ Rennes
Nicolas Mouchet: Univ Rennes
Héloïse M. Leclair: Univ Rennes
Lise Boussemart: Univ Rennes
Arthur Gautron: Univ Rennes
Laura Bachelot: Univ Rennes
Anthony Perrot: Univ Rennes
Anatoly Soshilov: University of California
Aljosja Rogiers: VIB
Florian Rambow: VIB
Erwan Dumontet: Univ Rennes
Karin Tarte: Univ Rennes
Alban Bessede: ImmuSmol
Gilles J. Guillemin: Macquarie University
Jean-Christophe Marine: VIB
Michael S. Denison: University of California
David Gilot: Univ Rennes
Marie-Dominique Galibert: Univ Rennes

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06951-2

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