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

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

SUBMITTER: Satoh TK 

PROVIDER: S-EPMC7269569 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature