Title: Abstract 5505: MyD88-dependent signaling decreases the anti-tumor efficacy of epidermal growth factor receptor inhibition in head and neck cancer cells
Abstract: Abstract 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 EGFR inhibitors (EGFRIs) despite tumor expression of EGFR. Gene expression analysis of erlotinib-treated HNSCC cell lines revealed an upregulation of genes involved in MyD88-dependent interleukin-6 (IL-6) expression compared to their respective vehicle treated cell lines. We therefore proposed that MyD88-dependent signaling may reduce the anti-tumor efficacy of the EGFR inhibitor erlotinib in HNSCC. Erlotinib significantly upregulated IL-6 secretion which we have previously reported to result in reduced drug efficacy and drug resistance (Fletcher et al, 2013). Suppression of MyD88 expression significantly blocked erlotinib-induced IL-6 secretion in vitro and increased the anti-tumor activity of erlotinib in vivo. There was little to no evidence of toll-like receptor (TLR) or interleukin-18 receptor (IL-18R) involvement in erlotinib-induced IL-6 secretion. However, suppression of the interleukin-1 receptor (IL-1R) signaling through pharmacologic and genetic methods significantly reduced erlotinib-induced IL-6 production and increased HNSCC cell sensitivity to erlotinib in vitro. 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 the EGFR antibody inhibitor cetuximab in vivo. Pre-treatment with a pan-caspase inhibitor but not a caspase-1 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 the MyD88-dependent signaling may improve the efficacy of EGFRIs in the treatment of HNSCC. Citation Format: Andrean L. Simons-Burnett, Adam T. Koch, Laurie Love-Homan, Aditya Stanam. MyD88-dependent signaling decreases the anti-tumor efficacy of epidermal growth factor receptor inhibition in head and neck cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5505. doi:10.1158/1538-7445.AM2015-5505
Publication Year: 2015
Publication Date: 2015-08-01
Language: en
Type: article
Indexed In: ['crossref']
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