Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma
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Aditya Stanam1,2, Katherine N. Gibson-Corley2,5,6, Laurie Love-Homan2, Nnamdi Ihejirika3, Andrean L. Simons1,2,4,5,6
1Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA
2Department of Pathology, The University of Iowa, Iowa City, IA, USA
3Lincoln University of the Commonwealth of Pennsylvania, Lincoln, PA, USA
4Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa City, IA, USA
5Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA
6Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
Andrean L. Simons, email: [email protected]
Keywords: interleukin-1, erlotinib resistance, interleukin-1 receptor antagonist, anakinra, head and neck squamous cell carcinoma
Received: May 20, 2016 Accepted: September 24, 2016 Published: October 12, 2016
Erlotinib has demonstrated poor clinical response rates for head and neck squamous cell carcinoma (HNSCC) to date and the majority of respondents acquire resistance to erlotinib relatively quickly. To elucidate novel pathways involved in erlotinib resistance, we compared the gene expression profiles of erlotinib-resistant (ER) vs. erlotinib-sensitive (ES) HNSCC cell lines. Enrichment analysis of microarray data revealed a deregulation of the IL-1 signaling pathway in ER versus ES-HNSCC cells. Gene expression of interleukin-1 alpha (IL1A) and interleukin-1 beta (IL1B) were significantly upregulated by > 2 fold in ER-SQ20B and ER-CAL 27 cells compared to their respective ES-cells. Secretion of the IL-1 receptor antagonist (IL-1RA) was significantly reduced in ER-cells compared to ES-cells. Blockade of IL-1 signaling using a recombinant IL-1R antagonist (anakinra) was able to inhibit the growth of ER-SQ20B and ER-CAL 27 but not ES-SQ20B and ES-CAL 27 xenografts as a single agent and in combination with erlotinib. ER-SQ20B xenografts treated with anakinra ± erlotinib were found to be less vascularized than ER-SQ20B xenografts treated with water or erlotinib. Mice bearing ER-SQ20B xenografts had significantly lesser circulating levels of G-CSF and IL-1β when treated with anakinra ± erlotinib compared to those treated with water or erlotinib alone. Furthermore, augmented mRNA levels of IL1A or interleukin-1 receptor accessory protein (IL1RAP) were associated with shortened survival in HNSCC patients. Altogether, blockade of the IL-1 pathway using anakinra overcame erlotinib resistance in HNSCC xenografts and may represent a novel strategy to overcome EGFR inhibitor resistance for treatment of HNSCC patients.
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