Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin.

Daniela Lulli,Maria Luigia Carbone,Saveria Pastore

doi:10.18632/oncotarget.10013

Daniela Lulli, Maria Luigia Carbone + Show 1 more

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https://doi.org/10.18632/oncotarget.10013

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Abstract

The Epidermal Growth Factor Receptor (EGFR) is centrally involved in the regulation of key processes of the epithelia, including cell proliferation, survival, differentiation, and also tumorigenesis. Humanized antibodies and small-molecule inhibitors targeting EGFR were developed to disrupt these functions in cancer cells and are currently used in the treatment of diverse metastatic epithelial cancers. By contrast, these drugs possess significant skin-specific toxic effects, comprising the establishment of a persistent inflammatory milieu. So far, the molecular mechanisms underlying these epiphenomena have been investigated rather poorly. Here we showed that keratinocytes respond to anti-EGFR drugs with the development of a type I interferon molecular signature. Upregulation of the transcription factor IRF1 is early implicated in the enhanced expression of interferon-kappa, leading to persistent activation of STAT1 and further amplification of downstream interferon-induced genes, including anti-viral effectors and chemokines. When anti-EGFR drugs are associated to TNF-α, whose expression is enhanced by the drugs themselves, all these molecular events undergo a dramatic enhancement by synergy mechanisms. Finally, high levels of interferon-kappa can be observed in epidermal keratinocytes and also in leukocytes infiltrating the upper dermis of cetuximab-driven skin lesions. Our data suggest that dysregulated activation of type I interferon innate immunity is implicated in the molecular processes triggered by anti-EGFR drugs and leading to persistent skin inflammation.

Highlights

Epidermal growth factor receptor (EGFR) inhibitors are increasingly used in monotherapy or in combination with chemo/radiotherapy for the treatment of diverse metastatic epithelial cancers [1]
In our search for pathogenic mechanisms underlying anti-EGFR drug-driven skin inflammation, we applied a whole-genome gene expression screening approach by Illumina microarrays (GSE74407), intentionally focusing on the combined use of the EGFR tyrosine kinase inhibitor PD168393 (PD16) and TNF-α rather than on the tyrosine kinase inhibitor alone
The most significant biological process activated by TNF-α at 6h time-point was cell-cell signaling as expected, with upregulated expression of a number of genes encoding for proteins of the IL-1 system (IL-1β, IL-36γ, IL-1ra, IL1R2), GM-CSF, the TNF-superfamily subunit lymphotoxin beta and chemokines (IL-8, CXCL10, CCL27, CCL20)

Summary

Introduction

Epidermal growth factor receptor (EGFR) inhibitors are increasingly used in monotherapy or in combination with chemo/radiotherapy for the treatment of diverse metastatic epithelial cancers [1]. Monoclonal antibodies such as cetuximab and panitumumab inhibit activation of the EGFR by partially occluding its extracellular ligand binding region, and by preventing the receptor from adopting the conformation required for dimerization and initiation of signal transduction [2, 3]. Within weeks from the first administration, EGFR inhibitors typically induce a papulopustular exanthema, histologically characterized by a dense superficial dermal inflammatory infiltrate surrounding hyperkeratotic and ectatic follicular infundibula. The infiltrate is initially formed of clusters of macrophages, dendritic cells and abundant lymphocytes, in the context of a progressive disruption of physical/ chemical and antimicrobial epidermal barriers due to keratinocyte dysfunction and/or death [7, 8]

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