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

H.C. Hawerkamp, A. Kislat, P.A. Gerber, M. Pollet, K.M. Rolfes, A.A. Soshilov, M.S. Denison, A.A. Momin, S.T. Arold, A. Datsi, S.A. Braun, P. Oláh, M.E. Lacouture, J. Krutmann, T. Haarmann-Stemmann, B. Homey, S. Meller
Allergy, (2019)

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

Keywords

Aryl hydricarbon receptor, Drug eruption, Lymphocyte activatrion test, Melanoma, Vemunafarib

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.

Code

DOI: 10.1111/all.13972

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