Oncotarget

Research Papers:

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

Daniela Lulli _, Maria Luigia Carbone and Saveria Pastore

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Oncotarget. 2016; 7:47777-47793. https://doi.org/10.18632/oncotarget.10013

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Abstract

Daniela Lulli1,*, Maria Luigia Carbone1,*, Saveria Pastore1

1Laboratory of Experimental Immunology, IDI-IRCCS, Fondazione Luigi M. Monti, Rome, Italy

*These authors have contributed equally to this work

Correspondence to:

Saveria Pastore, email: [email protected]

Keywords: anticancer drug, transcriptome profiling, tumor necrosis factor alpha, chemokine, antiviral innate immunity

Received: April 15, 2016    Accepted: May 29, 2016    Published: June 14, 2016

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.


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PII: 10013