IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are vital in treating solid cancers.
• Acneiform skin toxicities are common, severe side effects limiting EGFRi/MEKi therapy.
• The molecular basis of these skin toxicities remains largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying EGFRi/MEKi-induced acneiform skin toxicities.
• To identify key molecular mediators and pathways involved in the adverse skin reactions.

Main Methods:

• Gene expression profiling to identify candidate genes.
• Molecular and translational studies to validate findings in vitro and in vivo.
• Analysis of transcription factor binding sites and pathway activation.

Main Results:

• IL-36γ and IL-8 were identified as key drivers of EGFRi/MEKi skin toxicity.
• EGFRi/MEKi synergize with Cutibacterium acnes to induce IL-36γ in keratinocytes, followed by IL-8 production.
• This leads to cutaneous neutrophilia, a hallmark of acneiform eruptions.
• IL-36γ induction results from combined C. acnes-induced NF-κB activation and EGFRi/MEKi-mediated KLF4 expression.
• EGFRi/MEKi upregulate KLF4 via blockade of the EGFR/MEK/ERK pathway.

Conclusions:

• The study reveals a novel mechanism for EGFRi/MEKi-induced acneiform skin toxicity involving IL-36γ and KLF4.
• Cutibacterium acnes plays a crucial synergistic role with EGFRi/MEKi in driving skin inflammation.
• IL-36γ and KLF4 represent potential therapeutic targets to mitigate these adverse skin reactions.