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

Author

Listed:
  • Sébastien Corre

    (Univ Rennes)

  • Nina Tardif

    (Univ Rennes)

  • Nicolas Mouchet

    (Univ Rennes)

  • Héloïse M. Leclair

    (Univ Rennes)

  • Lise Boussemart

    (Univ Rennes
    Hospital University of Rennes (CHU Rennes))

  • Arthur Gautron

    (Univ Rennes)

  • Laura Bachelot

    (Univ Rennes)

  • Anthony Perrot

    (Univ Rennes)

  • Anatoly Soshilov

    (University of California)

  • Aljosja Rogiers

    (VIB
    KU Leuven)

  • Florian Rambow

    (VIB
    KU Leuven)

  • Erwan Dumontet

    (Univ Rennes)

  • Karin Tarte

    (Univ Rennes)

  • Alban Bessede

    (ImmuSmol)

  • Gilles J. Guillemin

    (Macquarie University)

  • Jean-Christophe Marine

    (VIB
    KU Leuven)

  • Michael S. Denison

    (University of California)

  • David Gilot

    (Univ Rennes)

  • Marie-Dominique Galibert

    (Univ Rennes
    Hospital University of Rennes (CHU Rennes))

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.

Suggested Citation

  • Sébastien Corre & Nina Tardif & Nicolas Mouchet & Héloïse M. Leclair & Lise Boussemart & Arthur Gautron & Laura Bachelot & Anthony Perrot & Anatoly Soshilov & Aljosja Rogiers & Florian Rambow & Erwan , 2018. "Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06951-2
    DOI: 10.1038/s41467-018-06951-2
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    Cited by:

    1. Karolína Ondrová & Iveta Zůvalová & Barbora Vyhlídalová & Kristýna Krasulová & Eva Miková & Radim Vrzal & Petr Nádvorník & Binod Nepal & Sandhya Kortagere & Martina Kopečná & David Kopečný & Marek Šeb, 2023. "Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Shuyan Dai & Lingzhi Qu & Jun Li & Ye Zhang & Longying Jiang & Hudie Wei & Ming Guo & Xiaojuan Chen & Yongheng Chen, 2022. "Structural insight into the ligand binding mechanism of aryl hydrocarbon receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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