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

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

Abstract

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-36 gamma 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-36 gamma in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36 gamma expression was the combined result of C. acnes-induced NF-kappa B activation and EGFRi/MEKi-mediated expression of the transcription factor Kriippel-like factor 4 (KLF4), due to the presence of both NF-kappa B and KLF4 binding sites in the human IL-36 gamma 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-36 gamma and the transcription factor KLF4 as potential therapeutic targets.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-9738
• Sprache: Englisch