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

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

doi:10.18632/oncotarget.12590

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

Journal article

Open access

Peer reviewed

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

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

Oncotarget, Vol.7(46), pp.76087-76100

11/15/2016

DOI: 10.18632/oncotarget.12590

PMCID: PMC5342798

PMID: 27738319

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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.

Prognosis

Carcinoma, Squamous Cell - genetics

Carcinoma, Squamous Cell - metabolism

Carcinoma, Squamous Cell - pathology

Humans

Gene Expression Regulation, Neoplastic

Transcriptome

Gene Expression Profiling

Head and Neck Neoplasms - metabolism

Squamous Cell Carcinoma of Head and Neck

Inflammation Mediators - metabolism

Antineoplastic Agents - pharmacology

Interleukin 1 Receptor Antagonist Protein - pharmacology

Disease Models, Animal

Cell Survival - drug effects

Interleukin-1 - metabolism

Cytokines - metabolism

Head and Neck Neoplasms - drug therapy

Angiogenesis Inhibitors - pharmacology

Head and Neck Neoplasms - pathology

Xenograft Model Antitumor Assays

Drug Resistance, Neoplasm - genetics

Animals

Carcinoma, Squamous Cell - drug therapy

Signal Transduction - drug effects

Erlotinib Hydrochloride - pharmacology

Survival Analysis

Cell Line, Tumor

Head and Neck Neoplasms - genetics

Mice

Protein Kinase Inhibitors - pharmacology

Analytical Core

Details

Title: Subtitle: Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma
Creators: Aditya Stanam - Department of Pathology, The University of Iowa, Iowa City, IA, USA
Katherine N Gibson-Corley - Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
Laurie Love-Homan - Department of Pathology, The University of Iowa, Iowa City, IA, USA
Nnamdi Ihejirika - Lincoln University of the Commonwealth of Pennsylvania, Lincoln, PA, USA
Andrean L Simons - Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Oncotarget, Vol.7(46), pp.76087-76100
DOI: 10.18632/oncotarget.12590
PMID: 27738319
PMCID: PMC5342798
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: United States
Grant note: P30 CA086862 / NCI NIH HHS R01 DE024550 / NIDCR NIH HHS
Language: English
Date published: 11/15/2016
Academic Unit: Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Iowa Superfund Research Program; Ophthalmology and Visual Sciences
Record Identifier: 9984047787902771

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