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, Marie Dominique Galibert

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)
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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.

Original languageEnglish
Article number4775
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 14 Nov 2018

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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