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

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          Abstract

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          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.

          Abstract

          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-1α, IL-8, and TNF-α 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-α 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-α 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.

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          Most cited references34

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          Mechanisms of cutaneous toxicities to EGFR inhibitors.

          The increased target specificity of epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is associated with the reduction or abolition of nonspecific and haematopoietic side effects. However, coincident inhibition of receptor activity in tissues that depend on EGFR signalling for normal function has undesirable consequences. Because of the key role of EGFR signalling in skin, dermatological toxicities have frequently been described with EGFRIs. The resultant significant physical and psycho-social discomfort might lead to interruption or dose modification of anticancer agents. There is an urgent need for an improved understanding of these toxicities to develop adequate staging systems and mechanistically driven therapies, and to ensure quality of life and consistent antineoplastic therapy.
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            The quest to overcome resistance to EGFR-targeted therapies in cancer.

            All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              EGFR antagonists in cancer treatment.

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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                25 October 2020
                November 2020
                : 12
                : 11
                : 3120
                Affiliations
                [1 ]Bio Process Development Team, Life Science Research Institute, Daewoong Pharmaceutical Co., Ltd., Yongin 17028, Korea; jmkim102@ 123456daewoong.co.kr (J.M.K.); syahn090@ 123456daewoong.co.kr (S.Y.A.); jec1113@ 123456daewoong.co.kr (J.E.C.)
                [2 ]Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea; jijunho@ 123456skku.edu
                [3 ]Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Korea; zoomboom@ 123456gilhospital.com
                [4 ]Department of Internal Medicine, Dong-A University Hospital, Busan 49201, Korea; sueelee@ 123456dau.ac.kr (S.L.); doctorhsj@ 123456dau.ac.kr (S.J.H.)
                [5 ]Department of Pulmonology, Dong-A University Hospital, Busan 49201, Korea; chshon@ 123456dau.ac.kr
                [6 ]Department of Internal Medicine, Gyeongsang National University Hospital, Jinju 52727, Korea; newatp@ 123456gnu.ac.kr
                [7 ]National Cancer Center, Department of Dermatology, Goyang 10408, Korea; khsong@ 123456ncc.re.kr
                [8 ]Department of Pathology, Dong-A University College of Medicine, Busan 49201, Korea
                Author notes
                [* ]Correspondence: drosy@ 123456dau.ac.kr (S.Y.O.); msroh@ 123456dau.ac.kr (M.S.R.); Tel.: +82-51-240-2808 (S.Y.O.); +82-51-240-2833 (M.S.R.); Fax: +82-51-246-5044 (S.Y.O.); +82-51-243-7396 (M.S.R.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-8321-4113
                https://orcid.org/0000-0001-5013-2683
                Article
                cancers-12-03120
                10.3390/cancers12113120
                7692663
                33113881
                31ecde29-3362-4962-b9af-c00cbd9f970c
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 September 2020
                : 22 October 2020
                Categories
                Article

                epidermal growth factor,epidermal growth factor inhibitor related skin rash,cetuximab,gefitinib

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