| First Author | Satoh TK | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 3 | Pages | 1417-1430 |
| PubMed ID | 31805013 | Mgi Jnum | J:298473 |
| Mgi Id | MGI:6480156 | Doi | 10.1172/JCI128678 |
| Citation | Satoh TK, et al. (2020) IL-36gamma drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes. J Clin Invest 130(3):1417-1430 |
| abstractText | 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-36gamma 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-36gamma in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36gamma expression was the combined result of C. acnes-induced NF-kappaB activation and EGFRi/MEKi-mediated expression of the transcription factor Kruppel-like factor 4 (KLF4), due to the presence of both NF-kappaB and KLF4 binding sites in the human IL-36gamma 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-36gamma and the transcription factor KLF4 as potential therapeutic targets. |
