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Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase

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Abstract

The family of human epidermal growth factor receptors (EGFR, HER2–4) exerts key functions in normal and malignant epithelial cells. Both EGFR and HER2 are valuable targets for anti-cancer drugs by interfering with ligand binding, receptor dimerization, or tyrosine kinase activity. A similar therapeutic strategy has been advocated for chronic psoriasis since plaque lesions overexpress EGFR and its ligands. Our aim was to characterize EGFR/HER2 protein expression in skin cultures and to evaluate the effects of tyrosine kinase inhibitors on epidermal outgrowth, morphology, and EGFR activation. Human skin explants were established on cell-free dermis and cultured at the air–liquid interface. The impact of small-molecule HER inhibitors on outgrowth was assayed by fluorescence-based image analysis and histometry. Effects of a dual EGFR/HER2 kinase inhibitor, PKI166, on neoepidermis were studied by immunohistochemistry and Western blot. Receptor immunostaining showed in vivo-like distributions with highest EGFR intensity in the proliferative layers whereas HER2 was mainly expressed by suprabasal keratinocytes. Reepithelialization was associated with EGFR autophosphorylation irrespective of exogenous ligand stimulation. PKI166 inhibited neoepidermal EGFR activation, keratinocyte proliferation, and outgrowth from normal and psoriatic skin explants. The rate of epidermalization in presence of other HER inhibitors varied suggesting that drug specificity, potency, and reversibility determine the dynamic outcome. Overall, agents predominantly targeting EGFR kinase were more efficient inhibitors of epidermal regeneration than an HER2-selective drug. The study illustrates the usefulness of a dynamic skin model and emphasizes the potential of HER-directed approaches to control epidermal growth in hyperproliferative skin disorders.

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Acknowledgments

We thank Inger Pihl-Lundin for skillful technical assistance and Lisa Wernroth at Uppsala Clinical Research Centre (UCR) for statistical expertise. The Department of Plastic Surgery, University Hospital, Uppsala, is acknowledged for supplying us with skin samples. Thanks are due to Pfizer, Novartis and AstraZeneca for generous supply of tyrosine kinase inhibitors. This study was supported by the Finsen Welander Foundation and the Swedish Psoriasis Association.

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  1. Department of Medical Sciences, Dermatology and Venereology, Uppsala University Hospital, 751 85, Uppsala, Sweden

    Sofi Forsberg & Ola Rollman

  2. Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden

    Arne Östman

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  1. Sofi Forsberg
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Correspondence to Ola Rollman.

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Forsberg, S., Östman, A. & Rollman, O. Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase. Arch Dermatol Res 300, 505–516 (2008). https://doi.org/10.1007/s00403-008-0853-2

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