Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events Journal Article
| Authors: | Hawerkamp, H. C.; Kislat, A.; Gerber, P. A.; Pollet, M.; Rolfes, K. M.; Soshilov, A. A.; Denison, M. S.; Momin, A. A.; Arold, S. T.; Datsi, A.; Braun, S. A.; Oláh, P.; Lacouture, M. E.; Krutmann, J.; Haarmann-Stemmann, T.; Homey, B.; Meller, S. |
| Article Title: | Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events |
| 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 (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. © 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; aged; human cell; nonhuman; flow cytometry; t lymphocyte; animal tissue; melanoma; drug eruption; gene expression; epidermal growth factor receptor; interleukin 1beta; animal experiment; protein interaction; in vitro study; rash; lymphocyte activation; gamma interferon; cyclooxygenase 2; upregulation; dermatitis; monocyte chemotactic protein 1; interleukin 22; tumor necrosis factor; aromatic hydrocarbon receptor; cytochrome p450 1a1; cxcl9 chemokine; thymus and activation regulated chemokine; cutaneous t cell attracting chemokine; rantes; aryl hydrocarbon receptor; vemurafenib; prostaglandin synthase; dabrafenib; cxcl14 chemokine; human; priority journal; article; macrophage derived chemokine; real time reverse transcription polymerase chain reaction; lymphocyte activation test; c-c motif chemokine 18; ccl1 chemokine |
| Journal Title: | Allergy: European Journal of Allergy and Clinical Immunology |
| Volume: | 74 |
| Issue: | 12 |
| ISSN: | 0105-4538 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2019-12-01 |
| Start Page: | 2437 |
| End Page: | 2448 |
| Language: | English |
| DOI: | 10.1111/all.13972 |
| PUBMED: | 31269229 |
| PROVIDER: | scopus |
| PMCID: | PMC6911016 |
| DOI/URL: | |
| Notes: | Source: Scopus |
