IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes

Satoh, Takashi K. and Mellett, Mark and Meier-Schiesser, Barbara and Fenini, Gabriele and Otsuka, Atsushi and Beer, Hans-Dietmar and Rordorf, Tamara and Maul, Julia-Tatjana and Hafner, Jürg and Navarini, Alexander A. and Contassot, Emmanuel and French, Lars E.. (2020) IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes. JCI The Journal of Clinical Investigation, 130 (3). pp. 1417-1430.

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Official URL: https://edoc.unibas.ch/73165/

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Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFR/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFR/MEKi skin toxicity. We provide molecular and translational evidence that EGFR/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C. acnes-induced NF-κB activation and EGFR/MEKi-mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-κB- and KLF4-binding sites in the human IL-36γ gene promoter. EGFR/MEKi increased KLF4 expression by blockade of the EGFR-MEK-ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFR/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie (Navarini)
UniBasel Contributors:Navarini, Alexander
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Clinical Investigation
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Jul 2020 12:07
Deposited On:13 Jul 2020 12:07

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