Mechanisms underlying skin disorders induced by EGFR inhibitors

Abstract

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is frequently mutated or overexpressed in a large number of tumors such as carcinomas or glioblastoma. Inhibitors of EGFR activation have been successfully established for the therapy of some cancers and are more and more frequently being used as first or later line therapies. Although the side effects induced by inhibitors of EGFR are less severe than those observed with classic cytotoxic chemotherapy and can usually be handled by out-patient care, they may still be a cause for dose reduction or discontinuation of treatment that can reduce the effectiveness of antitumor therapy. The mechanisms underlying these cutaneous side effects are only partly understood. Important questions, such as the reasons for the correlation between the intensity of the side effects and the efficiency of treatment with EGFR inhibitors, remain to be answered. Optimized adjuvant strategies to accompany anti-EGFR therapy need to be found for optimal therapeutic application and improved quality of life of patients. Here, we summarize current literature on the molecular and cellular mechanisms underlying the cutaneous side effects induced by EGFR inhibitors and provide evidence that keratinocytes are probably the optimal targets for adjuvant therapy aimed at alleviating skin toxicities.

Keywords: EGFR; barrier defect; cancer therapy; cetuximab; erlotinib; rash.

Figure 1.

Principles of EGFR activation and inhibition. (A) In the absence of ligand, EGFR remains in a conformation that inhibits dimerization. (B) Upon ligand binding, the resultant structural change allows homo- or hetero-dimerization with members of the ErbB family, resulting in autophosphorylation of the intracellular tyrosine kinase domain. Kinase activity induces phosphorylation of tyrosines at the C-terminal tail, inducing downstream signaling. (C, D) Therapeutic anti-EGFR antibodies bind the extracellular domain of EGFR and inhibit ligand binding (C), whereas tyrosine kinase inhibitors compete for ATP binding at the tyrosine kinase domain, thereby inhibiting kinase activity (D).

Figure 2.

Schematic representation of potential defects observed in the skin of EGFR-I–treated patients. (A) Alterations in chemokine and cytokine production in keratinocytes may result in attraction of inflammatory cells. (B) Disturbed keratinocyte differentiation impairs proper formation of tight junctions and barrier function. (C) The barrier defect and reduced expression of antimicrobial peptides result in bacterial infections accompanied by massive infiltration of neutrophil granulocytes and macrophages. These events often appear sequentially but may also occur independently. The graphic representation is modified from Lacouture M., Rodeck U., (DOI: 10.1126/scitranslmed.3006993)