Abstract
EGFR inhibition in keratinocytes increases chemokine expression and immune cell infiltration.
Major finding: EGFR inhibition in keratinocytes increases chemokine expression and immune cell infiltration.
Approach: Deletion of Egfr in the mouse epidermis serves as a model for EGFR inhibitor–induced skin rashes.
Impact: Use of these models may identify ways to avoid dose-limiting skin responses to EGFR inhibitors.
Small molecule and monoclonal antibody inhibitors of EGF receptor (EGFR) have shown clinical activity in EGFR-dependent cancers but cause skin toxicities such as acneiform rashes, dryness, itchiness, and infections. Such adverse events are currently the best predictors of antitumor activity, but they often negatively affect quality of life and lead to dose reduction or treatment discontinuation, which limits treatment efficacy. Mascia and colleagues analyzed the plasma of patients with ovarian cancer before and after treatment with gefitinib and noted increases in proinflammatory chemokine levels after treatment. Lichtenberger and colleagues similarly observed elevated chemokine expression in skin rash biopsies from EGFR inhibitor–treated patients compared with untreated healthy control subjects and also found evidence of increased bacterial colonization, decreased antimicrobial peptide expression, and skin barrier defects in affected patients. To gain insight into skin-specific effects of EGFR inhibition, both groups generated mouse models specifically lacking EGFR expression in epidermal keratinocytes and found that these mice progressively developed the phenotypic and histologic features of the skin lesions of EGFR inhibitor–treated patients. An early increase in proinflammatory chemokines was observed that promoted the recruitment of macrophages and mast cells, followed by infiltration of T cells, neutrophils, and eosinophils and defects in keratinocyte differentiation. Although both groups ruled out causative roles for lymphocytes and major immune signaling pathways in the EGFR-deficient skin phenotype, Mascia and colleagues found that bisphosphonate-mediated macrophage depletion partially rescued the phenotype of EGFR-deficient skin and normalized inflammatory gene expression, and Lichtenberger and colleagues observed that pharmacologic mast cell inhibition reduced infiltration of immune cells into the epidermis. Together, these findings provide insight into the role of EGFR in the epidermis and suggest potential approaches to prevent dose-limiting skin toxicities caused by EGFR inhibitors, which could improve the effectiveness of anti-EGFR therapy.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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