Adverse Events of anti-EGFR Therapy are Triggered by Hair Eruption and Commensal Skin Microbiota

EGFR targeted anti-cancer therapy induces severe skin toxicities, which affect life quality in patients. The lack of mechanistic details underlying these adverse events hampers their effective management. Here we identified EGFR as the epidermal master-regulator of the ERK pathway, which secures skin barrier integrity upon hair eruption. EGFR deficient epidermis displays a Th2-dominated expression signature and is permissive for excessive microbiota outgrowth. In the absence of EGFR, opening of the follicular ostia during hair eruption allows invasion of commensal microbiota aggravating barrier disruption and initiating an additional Th1 and Th17 response. Chronic folliculitis leads to Staphylococcus aureus dominated dysbiosis, further exacerbating inflammation and expanding barrier defects. Restoration of epidermal ERK signaling via therapeutic FGF7 treatment or transgenic SOS expression rescues skin barrier integrity in the absence of EGFR. These data reveal a gatekeeper function of the EGFR/ERK cascade in hair follicles securing the epidermal barrier around the erupting hair shaft. Overall design: Examination of treatment with antibiotics vs non treatment in wildtype, EGFR?ep, and K5-SOS mice