Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Induces Dry Skin via Decreased in Aquaporin-3 Expression.

Nobutomo Ikarashi,Riho Tanaka,Naoya Takayama,Takatoshi Yokoyama,Makana Yoshino,Risako Kon,Miho Kaneko,Tomofumi Watanabe,Hiroyasu Sakai,Junzo Kamei

doi:10.3390/biom10040545

Abstract

An adverse reaction of dry skin occurs frequently during treatment with anticancer epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). In this study, we conducted basic research to clarify the mechanism of EGFR-TKI-induced dry skin and propose new treatments or preventative measures. Dermal water content was significantly lower in the erlotinib-treated mice than in the control group. An assessment of the expression levels of functional genes in the skin revealed that only the expression of the water channel aquaporin-3 (AQP3) was significantly decreased in the erlotinib-treated group. When erlotinib was added to epidermal keratinocyte HaCaT cells, the expression levels of both AQP3 mRNA and protein decreased. Erlotinib treatment also significantly decreased the expression levels of phospho-EGFR and phospho-extracellular signal-regulated kinase (ERK), both in HaCaT cells and mouse skin. Dry skin due to erlotinib may be caused by the decreased expression of AQP3 in the skin, thereby limiting water transport from the vascular side to the corneum side. The decrease in AQP3 may also be attributable to ERK suppression via inhibition of EGFR activity by erlotinib. Therefore, substances that increase AQP3 expression may be effective for erlotinib-induced dry skin.

Highlights

Epidermal growth factor receptors (EGFRs) are intrinsic tyrosine kinase receptors expressed in the cell membranes of normal tissues in the skin, lungs, gastrointestinal tract, etc
The dermal water content and transepidermal water loss in the mice were measured on day 14 of erlotTinhieb dadermminaliswtraatteiornc.ontent and transepidermal water loss in the mice were measured on day 14 of erlAotisnigibniafidcmanitndisetcrraetiaosne.in the dermal water content by approximately 25% was noted in the erlotinib grouAp csoimgnpiafirceadnwt ditehctrheeasceonitnrotlhgerodueprm
TWhheesne rtehseuEltGs FsuRg-TgKesItgthefaittienrilbotwinaisbamdadyedsutoppHreasCsatTheceplhlsoisnphthoeryslaamtioenmoafnEnGerFRasaenrdloEtiRniKb,atnhde dexepcrreeassseioAnQlePv3eleoxpf AreQssPio3nminRNHAaCdaeTcrceeallsse.d significantly (Figure 5B). These results suggest that erlotinib may suppress the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) and decrease AQP3 expression in HaCaT cells

Summary

Introduction

Epidermal growth factor receptors (EGFRs) are intrinsic tyrosine kinase receptors expressed in the cell membranes of normal tissues in the skin, lungs, gastrointestinal tract, etc. EGFRs are overexpressed in various cancer cells [1], indicating their involvement in cancer cell growth, apoptosis survival, neoangiogenesis, and metastasis [2]. For this reason, the EGFR is a target molecule for inhibiting cancer cell growth, and various EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed for proactive use against refractory cancers [3,4,5]. Many patients complain of an acneiform rash or dry skin during erlotinib treatment. Suppression of dry skin can maximize the efficacy of erlotinib in cancer treatment

Methods

Results

Conclusion