Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

Aditya Stanam,Katherine N Gibson-Corley,Andrean L Simons,Laurie Love-Homan,Nnamdi Ihejirika

doi:10.18632/oncotarget.12590

Aditya Stanam, Katherine N Gibson-Corley + Show 3 more

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https://doi.org/10.18632/oncotarget.12590

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Abstract

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.

Highlights

Epidermal growth factor receptor (EGFR) is an important molecular target for antineoplastic therapy in head and neck squamous cell carcinoma (HNSCC) as it is found to be upregulated and overexpressed in the majority of HNSCCs and is associated with a poor clinical prognosis [1, 2, 3]
To investigate if an increased pro-inflammatory gene signature mediated by deregulated IL-1 signaling was involved in erlotinib resistance in HNSCC cells, gene expression analyses were performed on erlotinib-resistant (ER) and parental erlotinib-sensitive (ES) FaDu, CAL 27, SQ20B and SCC-25 HNSCC cells
We showed that ER-HNSCC cells demonstrate upregulated IL-1 signaling, and blockade of this pathway using anakinra overcame erlotinib resistance in vivo

Summary

Introduction

Epidermal growth factor receptor (EGFR) is an important molecular target for antineoplastic therapy in head and neck squamous cell carcinoma (HNSCC) as it is found to be upregulated and overexpressed in the majority of HNSCCs and is associated with a poor clinical prognosis [1, 2, 3]. In contrast to HNSCC, EGFR TKIs induce significant tumor regression in NSCLC patients, but www.impactjournals.com/oncotarget only in patients that harbor somatic mutations in exons of EGFR that code for the tyrosine kinase domain (~1535% of NSCLC patients) [8, 9]. These particular NSCLC patients still eventually acquire resistance to EGFR inhibitors despite their sensitizing EGFR mutation status [8, 9]. These particular EGFRsensitizing mutations are rarely observed in HNSCC tumors

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