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.

中文翻译：

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IL-36 γ由EGFR / MEK抑制和诱导共生驱动皮肤毒性Cutibacterium痤疮丙酸杆菌

表皮生长因子受体（EGFR）和MEK抑制剂（EGFRi / MEKi）对实体癌的治疗非常有益，但通常与严重的治疗限制的痤疮样皮肤毒性有关。潜在的分子机制了解甚少。使用基因表达谱，我们鉴定出IL-36γ和IL-8是EGFRi / MEKi皮肤毒性的候选驱动因子。我们提供分子和翻译的证据，EGFRi / MEKi与皮肤共生细菌痤疮痤疮痤疮协同作用，诱导角质形成细胞中的IL-36γ，随后诱导IL-8，导致皮肤中性粒细胞增多。IL-36γ表达是C的综合结果。痤疮诱导的NF-κB活化和EGFRi / MEKi介导的转录因子Krüppel样因子4（KLF4）的表达，这是由于人IL-36γ基因启动子中同时存在NF-κB和KLF4结合位点。EGFRi / MEKi通过阻断EGFR / MEK / ERK途径增加KLF4表达。这些结果为了解由EGFRi / MEKi诱导的痤疮样皮肤毒性的病理机制提供了见识，并确定了IL-36γ和转录因子KLF4作为潜在的治疗靶标。