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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., Introduction Agents targeting the epidermal growth factor receptor-mediated (EGFR-mediated) signaling pathway are increasingly used for the treatment of advanced lung, pancreatic, colorectal, and head and neck cancers, which benefit from [...]