Back to Search
Start Over
IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes
- Source :
- The Journal of Clinical Investigation
- Publication Year :
- 2020
- Publisher :
- American Society for Clinical Investigation, 2020.
-
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-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 Kruppel-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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Molecular biology
Inflammation
610 Medicine & health
Antineoplastic Agents
2700 General Medicine
Dermatology
Skin Diseases
03 medical and health sciences
Kruppel-Like Factor 4
0302 clinical medicine
Acneiform Eruptions
medicine
Humans
Epidermal growth factor receptor
Transcription factor
Protein Kinase Inhibitors
Skin
biology
business.industry
10177 Dermatology Clinic
Promoter
General Medicine
Neutrophilia
Gene expression profiling
ErbB Receptors
030104 developmental biology
KLF4
030220 oncology & carcinogenesis
10032 Clinic for Oncology and Hematology
Cancer research
biology.protein
Cytokines
medicine.symptom
business
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 15588238 and 00219738
- Volume :
- 130
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....70c9778b0b1a4057f72cb7f081a2c5ca