Publikation

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

Wissenschaftlicher Artikel/Review - 02.03.2020

Bereiche
PubMed
DOI
Kontakt

Zitation
Satoh T, Mellett M, Meier-Schiesser B, Fenini G, Otsuka A, Beer H, Rordorf T, Maul J, Hafner J, Navarini A, Contassot E, French L. IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes. J Clin Invest 2020; 130:1417-1430.
Art
Wissenschaftlicher Artikel/Review (Englisch)
Zeitschrift
J Clin Invest 2020; 130
Veröffentlichungsdatum
02.03.2020
eISSN (Online)
1558-8238
Seiten
1417-1430
Kurzbeschreibung/Zielsetzung

Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/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 EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/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 EGFRi/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. EGFRi/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 EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.