TY - JOUR
T1 - Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma
AU - Corre, Sébastien
AU - Tardif, Nina
AU - Mouchet, Nicolas
AU - Leclair, Héloïse M.
AU - Boussemart, Lise
AU - Gautron, Arthur
AU - Bachelot, Laura
AU - Perrot, Anthony
AU - Soshilov, Anatoly
AU - Rogiers, Aljosja
AU - Rambow, Florian
AU - Dumontet, Erwan
AU - Tarte, Karin
AU - Bessede, Alban
AU - Guillemin, Gilles J.
AU - Marine, Jean Christophe
AU - Denison, Michael S.
AU - Gilot, David
AU - Galibert, Marie Dominique
N1 - 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.
PY - 2018/11/14
Y1 - 2018/11/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056576501&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06951-2
DO - 10.1038/s41467-018-06951-2
M3 - Article
C2 - 30429474
AN - SCOPUS:85056576501
SN - 2041-1723
VL - 9
SP - 1
EP - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4775
ER -