期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 3, 页码 1417-1430出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI128678
关键词
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资金
- Swiss National Science Foundation [310030-176035]
- Zurich University Research Priority Program Translational Cancer Research
- Rare Disease Initiative Zurich (RADIZ)
- Novartis Foundation for Medical-Biological Research
- Clinical Research Priority Program for Rare Diseases
- University of Zurich
- Monique Dornonville de la Cour Foundation
- Swiss National Science Foundation (SNF) [310030_176035] Funding Source: Swiss National Science Foundation (SNF)
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 Kriippel-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.
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