Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events. Issue 12 (3rd September 2019)

• Record Type: Journal Article
• Authors: 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; Haarmann‐Stemmann, Thomas; Homey, Bernhard; Meller, Stephan
• Is Part Of: Allergy. Volume 74:Issue 12(2019)
• Page Start: 2437
• Page End: 2448
• Publication Date: 2019-09-03
• Subjects: aryl hydrocarbon receptor -- drug eruption -- lymphocyte activation test -- melanoma -- vemurafenib; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.13972
• Languages: English
• ISSNs: 0105-4538

Abstract

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. Abstract : Vemurafenib‐induced rashes are characterized by an increased expression of IFNG, TNFA, and chemokines including CCL5, CXCL9, CXCL10 and CXCL11. Vemurafenib acts aryl hydrocarbon receptor (AHR) as antagonist by inhibiting AhR translocation to the nucleus and leading to downregulation of cytochrome P450 family 1 subfamilyA member 1 (CYP1A1). Vemurafenib induces IL‐17 and IFN‐γ expression in T cells, while inhibiting IL‐22 expression.