IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes.
J Clin Invest
; 130(3): 1417-1430, 2020 03 02.
Article
in En
| MEDLINE
| ID: mdl-31805013
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 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Propionibacteriaceae
/
Interleukin-1
/
Skin Diseases, Bacterial
/
MAP Kinase Signaling System
/
ErbB Receptors
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Clin Invest
Year:
2020
Document type:
Article
Affiliation country:
Switzerland