Journal Article

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

Meier-Schiesser, Mark MelletBarbara, Beer, Hans-Dietmar, Hafner, Jurg, Contasso, Emmanuel, Rordorf, Tamara, Fenini, Gabriele, Navarini, Alexander A, Otsuka, Atsushi, Satoh, Takashi K, Maul, Julia-Tatjana, French, Lars E

2020

Overview

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 Kruppel-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.

• Publisher: American Society for Clinical Investigation
• Subject: Acne / Biochemistry / Cancer treatment / Cetuximab / Criminal investigation / Dermatologic agents / Epidermal growth factors / Gene expression / Genes / Motor vehicle drivers / Neutrophilia / Scientific equipment industry / Skin / Skin care / Toxicity