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

doi:10.1038/s41467-018-06951-2

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 journal › Article › peer-review

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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 language	English
Article number	4775
Pages (from-to)	1-13
Number of pages	13
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06951-2
Publication status	Published - 14 Nov 2018

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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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Corre, S., Tardif, N., Mouchet, N., Leclair, H. M., Boussemart, L., Gautron, A., Bachelot, L., Perrot, A., Soshilov, A., Rogiers, A., Rambow, F., Dumontet, E., Tarte, K., Bessede, A., Guillemin, G. J., Marine, J. C., Denison, M. S., Gilot, D., & Galibert, M. D. (2018). Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nature Communications, 9(1), 1-13. Article 4775. https://doi.org/10.1038/s41467-018-06951-2

@article{aaadfa6065054bc3b02df4ef6ceb529c,

title = "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.",

author = "S{\'e}bastien Corre and Nina Tardif and Nicolas Mouchet and Leclair, \{H{\'e}lo{\"i}se M.\} and Lise Boussemart and Arthur Gautron and Laura Bachelot and Anthony Perrot and Anatoly Soshilov and Aljosja Rogiers and Florian Rambow and Erwan Dumontet and Karin Tarte and Alban Bessede and Guillemin, \{Gilles J.\} and Marine, \{Jean Christophe\} and Denison, \{Michael S.\} and David Gilot and Galibert, \{Marie Dominique\}",

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.",

year = "2018",

month = nov,

day = "14",

doi = "10.1038/s41467-018-06951-2",

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Corre, S, Tardif, N, Mouchet, N, Leclair, HM, Boussemart, L, Gautron, A, Bachelot, L, Perrot, A, Soshilov, A, Rogiers, A, Rambow, F, Dumontet, E, Tarte, K, Bessede, A, Guillemin, GJ, Marine, JC, Denison, MS, Gilot, D & Galibert, MD 2018, 'Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma', Nature Communications, vol. 9, no. 1, 4775, pp. 1-13. https://doi.org/10.1038/s41467-018-06951-2

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 - https://www.scopus.com/pages/publications/85056576501

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 -

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

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