title: Genetic ablation of epidermal EGFR reveals the dynamic origin of adverse effects of anti-EGFR therapy.
abstract: 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.
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Francesca
authors: F
authors: Mascia
authors: Gary
authors: G
authors: Lam
authors: Christopher
authors: C
authors: Keith
authors: Caroline
authors: C
authors: Garber
authors: Seth M
authors: SM
authors: Steinberg
authors: Elise
authors: E
authors: Kohn
authors: Stuart H
authors: SH
authors: Yuspa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001772:Blood Cell Count; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics*; D005076:Exanthema / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D005260:Female; D000077156:Gefitinib; D018773:Genes, erbB-1; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011799:Quinazolines / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D018836:Inflammation Mediators; D011799:Quinazolines; D012333:RNA, Messenger; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D000077156:Gefitinib
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