EGFR is upregulated in the majority of
head and neck squamous cell carcinomas (
HNSCC). However, many patients with
HNSCC respond poorly to the EGFR inhibitors (EGFRI)
cetuximab and
erlotinib, despite
tumor expression of EGFR. Gene expression analysis of
erlotinib-treated
HNSCC cells revealed an upregulation of genes involved in MyD88-dependent signaling compared with their respective vehicle-treated cell lines. We therefore investigated whether MyD88-dependent signaling may reduce the antitumor efficacy of EGFRIs in
HNSCC.
Erlotinib significantly upregulated
IL6 secretion in
HNSCC cell lines, which our laboratory previously reported to result in reduced
drug efficacy. Suppression of MyD88 expression blocked
erlotinib-induced
IL6 secretion in vitro and increased the antitumor activity of
erlotinib in vivo. There was little evidence of
Toll-like receptor or
IL18 receptor involvement in
erlotinib-induced
IL6 secretion. However, suppression of IL1R signaling significantly reduced
erlotinib-induced
IL6 production. A time-dependent increase of IL1α but not IL1β was observed in response to
erlotinib treatment, and IL1α blockade significantly increased the antitumor activity of
erlotinib and
cetuximab in vivo. A pan-
caspase inhibitor reduced
erlotinib-induced IL1α secretion, suggesting that IL1α was released because of cell death. Human
HNSCC tumors showed higher IL1α
mRNA levels compared with matched normal tissue, and IL1α was found to be negatively correlated with survival in patients with
HNSCC. Overall, the IL1α/IL1R/MYD88/
IL6 pathway may be responsible for the reduced antitumor efficacy of
erlotinib and other EGFRIs, and blockade of IL1 signaling may improve the efficacy of EGFRIs in the treatment of
HNSCC.