rhEGF Treatment Improves EGFR Inhibitors-Induced Skin Barrier and Immune Defects

Abstract

Background: The mechanisms of epidermal growth factor (EGF) effects EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF’s positive effects. Methods: Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). The expression levels of skin barrier related proteins, inflammatory cytokines, and antimicrobial peptides (AMPs) were measured by using RT qPCR, ELISA, immunohistochemical (IHC) stain, or immunofluorescence..Results: Using western blot assay, cetuximab decreased EGFR and phosphorylated EGFR (pEGFR) expression. In contrast, rhEGF increased EGFR and pEGFR expression. Also, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. Expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRIs -treated tissue. However, in rhEGF and EGFRIs co-treated tissue, those expressions were increased. Pro-inflammatory cytokines, including IL-1α, IL-8, and TNF-α expression, were increased by EGFRIs, and down-regulated by rhEGF. In patients’ tissue evaluation, compared with control, patients’ Ki-67 and EGFR expression were decreased (P=0.015, P=0.001). Patients’ IL-17 and TNF-α expression intensity was higher than that of control group (P=0.038, P=0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely patients’ proportions of IL-17 and TNF-α were decreased to low stain level.Conclusions: Treatment of rhEGF improved EGFRIs-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.