Erlotinib-Induced Skin Inflammation Is IL-1 Mediated in KC-Tie2 Mice and Human Skin Organ Culture

Abstract

Epidermal growth factor receptor (EGFR) is the prototypical member of the ErbB network comprised of four transmembrane receptor tyrosine kinases (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4). These receptors bind EGF and heregulin family ligands in a dynamic, feedback-regulated fashion, activating multiple signal transduction pathways and ultimately affecting many cellular functions (Avraham and Yarden, 2011; Wilson et al., 2009). ErbB receptors and their ligands are overexpressed in a wide spectrum of hyperplastic epithelial disorders including psoriasis and cancers. Numerous monoclonal antibodies and receptor tyrosine kinase inhibitors have been designed to block their activation (Yarden and Pines, 2012), and are highly effective for treating colorectal and non-small cell lung cancers. However, skin toxicity is frequently observed in patients undergoing therapy with EGFR inhibitors (EGFRIs) (Lacouture, 2006), including papular and pustular eruptions of the face and trunk, nail changes, dry skin, itch, and hair loss (Lacouture and Lai, 2006). These side-effects are the major dose-limiting toxicity of EGFRI therapy (Boone et al., 2007) and emphasize the importance of understanding the mechanisms involved.