title: Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma.
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.
authors.affiliation: Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA.|Department of Pathology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Stanam
authors.affiliation: Department of Pathology, The University of Iowa, Iowa City, IA, USA.|Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA.|Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Gibson-Corley
authors.affiliation: Department of Pathology, The University of Iowa, Iowa City, IA, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Love-Homan
authors.affiliation: Lincoln University of the Commonwealth of Pennsylvania, Lincoln, PA, USA.
authors.forename: Nnamdi
authors.initials: N
authors.lastname: Ihejirika
authors.affiliation: Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA.|Department of Pathology, The University of Iowa, Iowa City, IA, USA.|Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa City, IA, USA.|Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA.|Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
authors.forename: Andrean L
authors.initials: AL
authors.lastname: Simons
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride
keywords: anakinra; erlotinib resistance; head and neck squamous cell carcinoma; interleukin-1; interleukin-1 receptor antagonist