Human keratinocytes were recently shown to respond to anti-EGFR (
epidermal growth factor receptor) drugs with activation of an
interferon-κ-driven autocrine loop, leading to enhanced expression of innate
antiviral effectors and of the pro-inflammatory
chemokines CXCL10 (C-X-C motif
chemokine 10) and CCL2 (C-C motif
ligand 2). Here we showed active
type I interferon signaling in the skin lesions of
cancer patients undergoing treatment with the anti-EGFR drug
cetuximab. Strong nuclear positivity for
Interferon Regulatory Factor 1 and phosphorylated
Signal Transducer and Activator of Transcription 1, enhanced
interferon-κ expression and CXCL10 was associated to the epidermal compartment. Notably, 50 micromolar
resveratrol and
quercetin fully suppressed the low constitutive levels of
type I interferon signaling and prevented its activation by the anti-EGFR
cetuximab or
gefitinib in cultured keratinocytes. In sensitized mice undergoing
DNFB (2,4-dinitro-1-fluorobenzene)-induced
contact hypersensitivity, local administration of
gefitinib prior to elicitation further amplified
hapten-induced
type I interferon activation, tissue
edema, and infiltration by T cells, whereas
resveratrol or
quercetin suppressed this inflammatory cascade. Overall, these data suggest that topical application of
resveratrol or
quercetin could be potentially effective in preventing pathological conditions due to overactivation of type I IFN (
interferon)-driven circuits in the skin, including the inflammatory manifestations of anti-EGFR drug-induced skin-targeted toxicity.