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Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events
Author(s) -
Hawerkamp Heike C.,
Kislat Andreas,
Gerber Peter A.,
Pollet Marius,
Rolfes Katharina M.,
Soshilov Anatoly A.,
Denison Michael S.,
Momin Afaque A.,
Arold Stefan T.,
Datsi Angeliki,
Braun Stephan A.,
Oláh Péter,
Lacouture Mario E.,
Krutmann Jean,
HaarmannStemmann Thomas,
Homey Bernhard,
Meller Stephan
Publication year - 2019
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.13972
Subject(s) - vemurafenib , proinflammatory cytokine , aryl hydrocarbon receptor , medicine , cancer research , context (archaeology) , melanoma , immunology , pharmacology , inflammation , biology , transcription factor , biochemistry , metastatic melanoma , gene , paleontology
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 (eg, TNF ) and chemokines (eg, CCL5 ). In line with these results, we observed an impaired expression of AhR‐regulated genes (eg, 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 toward a potential role for topical AhR agonists in supportive cancer care.