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

Abstract

Simple Summary In our prior study, we demonstrated that recombinant human epidermal growth factor (rhEGF) treatment is effective for managing epidermal growth factor receptor inhibitors (EGFRIs)-related skin toxicities and improves patients' quality of life (QoL) compared with placebo. Nevertheless, the mechanisms of rhEGF effects are unknown yet so basic study is needed to clarify the mechanisms. In this study, we revealed that treatment of rhEGF in human epidermal keratinocytes, 3d-cultured human skin tissue and patient lesions improved EGFRIs-induced skin eruption via normalizing proliferation and differentiation of keratinocytes, reducing inflammatory cytokines expression and inducing expression of AMPs. These findings provided an evidence for the use of rhEGF as a treatment for skin side effects derived from EGFRI. The mechanisms of epidermal growth factor (EGF) affecting EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF's positive effects. Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). As a result, rhEGF increased EGFR and pEGFR expression. Furthermore, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. In addition, rhEGF bound to EGFR after than cetuximab, but cetuximab bound to EGFR more strongly than rhEGF. Moreover, expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRI-treated tissue. However, in rhEGF and EGFRI co-treated tissue, those expressions were increased. Expression of IL-1 alpha, IL-8, and TNF-alpha was increased by EGFRIs and down-regulated by rhEGF. Furthermore, hBD-2 and hBD-3 protein expressions were inhibited by cetuximab or gefitinib treatment, and those decrements were increased by rhEGF treatment. In patients' tissue evaluation, compared with controls, patients' Ki-67 and EGFR expression were decreased (p = 0.015, p = 0.001). Patients' IL-17 and TNF-alpha expression intensity was higher than that of the 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-alpha were decreased to low stain level. In conclusion, treatment of rhEGF improved EGFRI-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.