Novel acquisitions on the immunoprotective roles of the EGF receptor in the skin

Abstract

The EGF receptor (EGFR) and its ligands represent one of the most powerful and complex signaling networks in higher vertebrates. This system exerts an unusually wide spectrum of diverse bioregulatory functions. Numerous indications have been collected in the past decades, essentially based on mouse models, that emphasize its central role in the development and homeostasis of the skin. In particular, the multiple phenotypes of mouse models with distinct dysregulations of the EGFR pathway indicate clearly that this system exerts a major impact on keratinocyte proliferation and differentiation and, eventually, on the process of wound healing, hair follicle morphogenesis and malignant transformation [1]. Notably, despite a long history of robust investigation into the diverse biological outcomes deriving from its possible dysfunctions in vivo in the mouse, a novel and, at least in part, unprecedented compendium of the role of EGFR in human skin is now emerging from the widespread use of EGFR inhibitors in the therapy of EGFR-dependent tumors. Currently, a humanized anti-EGFR monoclonal antibody (cetuximab), a fully human monoclonal antibody (panitumumab) and two smallmolecule EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) are available for the treatment of four metastatic epithelial cancers: non-small-cell lung cancer, squamous cell carcinoma of the head and neck, colorectal cancer and pancreatic cancer [2]. In patients treated with these drugs, a common adverse effect is a cutaneous inflammatory rash, characterized by papular pustular or acneiform eruption, which can be severe enough to lead to treatment modification or cessation [3]. These skin lesions are frequently pruritic and mostly affect the face and the upper trunk, although they may affect areas such as the dorsal arms and lower legs, and respond to anti-inflammatory drugs. Data from a large number of clinical trials suggest that the presence and severity of this cutaneous toxic effect are the most important positive correlates and predictors of the efficacy of anti-EGFR therapy in terms of progression-free survival [2,3]. Nonetheless, there is a serious need for an improved understanding of this side