Role of the AHR in cutaneous adverse drug reactions

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Adverse drug reactions (ADR) are common and often represent a serious threat to patients’ health and that may compromise their treatment continuation. ADR are mostly classified in on-target and off-target reactions. On-target reactions are very common and are caused by an augmentation of the known therapeutic and pharmacological action of a medication. In contrast, off-target reactions consist of unpredictable immune and non-immune reactions. Off-target non-immune ADR may involve innate immune responses but are not based on a specific hypersensitivity due to an immunological memory. Recently, the applicant and his collaborators demonstrated that vemurafenib antagonizes the canonical aryl hydrocarbon receptor (AHR) signaling pathway resulting in the development of an off-target non-immune reaction presenting as inflammatory skin rashes or phototoxic reactions. The AHR is a transcriptional factor that orchestrates multiple functions following its activation by a variety of ligands including xenobiotics, natural products, microbiome metabolites, and (pseudo-) endogenous molecules. Apart from skin homeostasis, the AHR pathway controls immune-mediated skin responses and is also involved in cutaneous pathological processes such as atopic dermatitis and plaque psoriasis. Moreover, the AHR pathway regulates the metabolism of common drugs. Activation of AHR stimulates canonical and non-canonical pathways. The canonical and the non-canonical AHR signaling pathways are tightly balanced in healthy skin thereby contributing to skin homeostasis. Preliminary unpublished data demonstrate that not only vemurafenib but also several other drugs present as AHR ligands and display antagonistic activity against the AHR in vitro. In the proposed project the applicant aims to characterize the role of the AHR in ADR and put forward the concept of modulating of AHR activity as a new mechanism of an off-target non-immune ADR. For this purpose, the applicant will first use empirical data as well as in silico-prediction models to identify drugs interfering with AHR-signaling (aim #1), second confirm the biologic effects of AHR-antagonistic drugs (aim #2), third validate AHR antagonism signatures in biomaterial of ADR patients ex vivo (aim #3), and fourth establish a diagnostic cell-based tool to identify AHR-mediated drug eruptions in vitro (aim #4). The experimental methods are established in the laboratories of the applicant, his collaborators or at the core facilities of the University of Düsseldorf. Significance of the project: The proposed project will identify clinically relevant drugs that interfere with AHR signaling. Findings of this project will increase our understanding of molecular and cellular pathways inducing ADR based on an off-target non-immune ADR. The results will provide new translational concepts to improve the clinical management of ADR.