Abstract
Introduction: In recent years, BRAF protein kinase inhibitor vemurafenib has been successfully established for the treatment of advanced malignant 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.
Material and Methods: To characterize vemurafenib-induced rashes we performed immunohistochemical and gene expression analysis of lesional skin sections of vemurafenib-treated patients. Lymphocyte activation tests (LAT) were conducted to detect vemurafenib-specific T cells. Furthermore, we stimulated T cells, keratinocytes and skin explants from healthy donors with different concentrations of vemurafenib and evaluated the gene expression profile on mRNA and protein levels. Finally, the aryl hydrocarbon receptor antagonism was investigated using different cell-free protein interaction assays.
Results: Vemurafenib-induced skin rashes are characterized by a massive infiltration and clustering of T cells (CD4+ and CD8+), CD68+ macrophages, mast cells as well as intraepidermal CD1a+ Langerhans cells, whereas eosinophils were not detected. 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, IL1B) 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.
Conclusions: Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of 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.