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

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.
Complete list of metadatas

Cited literature [65 references]  Display  Hide  Download

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01972443
Contributor : Laurent Jonchère <>
Submitted on : Friday, July 12, 2019 - 2:53:05 PM
Last modification on : Wednesday, August 7, 2019 - 12:19:20 PM

File

s41467-018-06951-2.pdf
Publisher files allowed on an open archive

Identifiers

Citation

Sébastien Corre, Nina Tardif, Nicolas Mouchet, Heloise M. Leclair, Lise Boussemart, et al.. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nature Communications, Nature Publishing Group, 2018, 9, pp.4775. ⟨10.1038/s41467-018-06951-2⟩. ⟨hal-01972443⟩

Share

Metrics

Record views

87

Files downloads

38