MyD88-dependent signaling decreases the anti-tumor efficacy of epidermal growth factor receptor inhibition in head and neck cancer cells

Epidermal growth factor receptor (EGFR) is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). However many HNSCC patients respond poorly to the EGFR inhibitors (EGFRIs) 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 to their respective vehicle-treated cell lines. We therefore investigated if MyD88-dependent signaling may reduce the anti-tumor efficacy of EGFRIs in HNSCC. Erlotinib significantly upregulated interleukin-6 (IL-6) secretion in HNSCC cell lines which our laboratory previously reported to result in reduced drug efficacy. Suppression of MyD88 expression blocked erlotinib-induced IL-6 secretion in vitro and increased the anti-tumor activity of erlotinib in vivo . There was little evidence of toll-like receptor or interleukin-18 receptor involvement in erlotinib-induced IL-6 secretion. However, suppression of interleukin-1 receptor (IL-1R) signaling significantly reduced erlotinib-induced IL-6 production. A time-dependent increase of IL-1 alpha (IL-1α) but not IL-1 beta (IL-1β) was observed in response to erlotinib treatment and IL-1α blockade significantly increased the anti-tumor activity of erlotinib and cetuximab in vivo . A pan-caspase inhibitor reduced erlotinib-induced IL-1α secretion suggesting that IL-1α was released due to cell death. Human HNSCC tumors showed higher IL-1α mRNA levels compared to matched normal tissue, and IL-1α was found to be negatively correlated with survival in HNSCC patients. Overall, the IL-1α/IL-1R/MYD88/IL-6 pathway may be responsible for the reduced anti-tumor efficacy of erlotinib and other EGFRIs; and blockade of IL-1 signaling may improve the efficacy of EGFRIs in the treatment of HNSCC.