Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events.
AuthorsHawerkamp, Heike C
Gerber, Peter A
Rolfes, Katharina M
Soshilov, Anatoly A
Denison, Michael S
Momin, Afaque Ahmad Imtiyaz
Arold, Stefan T.
Braun, Stephan A
Lacouture, Mario E
KAUST DepartmentBioscience Program
Computational Bioscience Research Center (CBRC)
Biological and Environmental Sciences and Engineering (BESE) Division
KAUST Grant NumberFCC/1/1976-25
Embargo End Date2020-07-04
Permanent link to this recordhttp://hdl.handle.net/10754/656463
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AbstractBACKGROUND: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.
CitationHawerkamp, 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
SponsorsWe 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.