Genetic Ablation of Epidermal EGFR Reveals the Dynamic Origin of Adverse Effects of Anti-EGFR Therapy

Epidermal EGFR ablation causes a localized cutaneous rash and a systemic inflammatory syndrome. Skin-Deep Search for the Effects of EGFR Inhibitors The goal of all medical interventions is to treat disease while minimizing the damage to healthy tissues in the body. This can be difficult to achieve for cancer drugs, however, especially when the effectiveness of a drug directly correlates with its side effects, as is the case for inhibitors of the epidermal growth factor receptor (EGFR). EGFR inhibitors are particularly known for causing a severe rash and skin damage, which sometimes forces patients to prematurely stop their treatments. Now, two papers by Mascia et al. and Lichtenberger et al. help clarify the mechanism of rash formation induced by EGFR inhibitors and uncover some of the skin components that contribute to this phenomenon. Both sets of authors used mouse models that lack EGFR only in the skin to replicate the pattern of injury seen in patients treated with EGFR inhibitors. They characterized the changes in chemokine expression in the skin of treated patients and study animals and examined the effects of EGFR inhibition on skin defenses and bacteria. They also investigated the effects of crossing mice that lack EGFR in the skin with mice deficient in different immune pathways and immune cell types to determine which ones are necessary for the rash phenotype. The findings of these two studies suggest that EGFR signaling is important for normal skin barrier function and antimicrobial defense and that skin macrophages may contribute to the adverse effects of EGFR inhibitors. Additional work will be necessary to further expand our understanding of EGFR inhibitor toxicity and to continue the search for ways to prevent this disruptive side effect. The current studies provide mechanistic insights that should help guide further investigation in this area. Cancer patients treated with anti-EGFR (epidermal growth factor receptor) drugs often develop a dose-limiting pruritic rash of unknown etiology. The aims of our study were to define causal associations from a clinical study of cutaneous and systemic changes in patients treated with gefitinib and use these to develop and characterize a mouse model that recapitulates the human skin rash syndrome caused by anti-EGFR therapy. We examined the patients’ plasma before and after treatment with gefitinib and documented changes in chemokines and leukocyte counts associated with the extent of rash or the presence of pruritus. We established a parallel mouse model by ablating EGFR in the epidermis. These mice developed skin lesions similar to the human rash. Before lesion development, we detected increased mRNA expression of chemokines in the skin associated with early infiltration of macrophages and mast cells and later infiltration of eosinophils, T cells, and neutrophils. As the skin phenotype evolved, changes in blood counts and circulating chemokines reproduced those seen in the gefitinib-treated patients. Crossing the mutant mice with mice deficient for tumor necrosis factor–α (TNF-α) receptors, MyD88, NOS2, CCR2, T cells, or B cells failed to reverse the skin phenotype. However, local depletion of macrophages provided partial resolution, suggesting that this model can identify targets that may be effective in preventing the troublesome and dose-limiting skin response to anti-EGFR drugs. These results highlight the importance of EGFR signaling in maintaining skin immune homeostasis and identify a macrophage contribution to a serious adverse consequence of cancer chemotherapy.