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    Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events.

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    Name:
    Hawerkamp_et_al-2019-Allergy.pdf
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    Description:
    Accepted manuscript
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    Type
    Article
    Authors
    Hawerkamp, Heike C
    Kislat, Andreas
    Gerber, Peter A
    Pollet, Marius
    Rolfes, Katharina M
    Soshilov, Anatoly A
    Denison, Michael S
    Momin, Afaque Ahmad Imtiyaz cc
    Arold, Stefan T. cc
    Datsi, Angeliki
    Braun, Stephan A
    Oláh, Péter
    Lacouture, Mario E
    Krutmann, Jean
    Haarmann-Stemmann, Thomas
    Homey, Bernhard
    Meller, Stephan
    KAUST Department
    Bioscience Program
    Computational Bioscience Research Center (CBRC)
    Biological and Environmental Sciences and Engineering (BESE) Division
    KAUST Grant Number
    FCC/1/1976-25
    Date
    2019-07-03
    Embargo End Date
    2020-07-04
    Permanent link to this record
    http://hdl.handle.net/10754/656463
    
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    Abstract
    BACKGROUND:In recent years, the BRAF-inhibitor vemurafenib has been successfully established in the therapy of advanced melanoma. Despite its superior efficacy, the use of vemurafenib is limited by frequent inflammatory cutaneous adverse events that affect patients' quality of life and may lead to dose reduction or even cessation of anti-tumor therapy. To date, the molecular and cellular mechanisms of vemurafenib-induced rashes have remained largely elusive. METHODS:In this study we deployed immunohistochemistry, RT-qPCR, flow cytometry, lymphocyte activation tests and different cell-free protein-interaction assays. RESULTS:We here demonstrate that vemurafenib inhibits the downstream signaling of the canonical pathway of aryl hydrocarbon receptor (AhR) in vitro, thereby inducing the expression of proinflammatory cytokines (e.g. TNF) and chemokines (e.g. CCL5). In line with these results we observed an impaired expression of AhR regulated genes (e.g. CYP1A1) and an upregulation of the corresponding proinflammatory genes in vivo. Moreover, results of lymphocyte activation tests showed the absence of drug-specific T cells in respective patients. CONCLUSION:Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of canonical AhR signaling. Our findings contribute to our understanding of the central role of the AhR in skin inflammation and may point towards a potential role for topical AhR agonists in supportive cancer care. This article is protected by copyright. All rights reserved.
    Citation
    Hawerkamp, H. C., Kislat, A., Gerber, P. A., Pollet, M., Rolfes, K. M., Soshilov, A. A., … Meller, S. (2019). Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events. Allergy. doi:10.1111/all.13972
    Sponsors
    We thank Paul Chapman and Katja Schindler for providing clinical images and proofreading the manuscript and Katarina Gradin and Lorenz Poellinger for generously providing the XRE-HepG2 reporter cell line. The research by Stefan T. Arold and Afaque A. Momin was supported by the King Abdullah University of Science and Technology (KAUST)through the Award No. FCC/1/1976-25, from the Office of Sponsored Research (OSR). Mario E. Lacouture is funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Thomas Haarmann-Stemmann and Katharina M. Rolfes were supported by grants of the Deutsche Forschungsgemeinschaft (HA 7346/2-1) and the Jürgen Manchot Foundation.
    Publisher
    Wiley
    Journal
    Allergy
    DOI
    10.1111/all.13972
    Additional Links
    https://onlinelibrary.wiley.com/doi/abs/10.1111/all.13972
    ae974a485f413a2113503eed53cd6c53
    10.1111/all.13972
    Scopus Count
    Collections
    Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC)

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