title: Upregulated interleukin-6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma.
abstract: Despite the role of epidermal growth factor receptor (EGFR) signaling in head and neck squamous cell carcinoma (HNSCC) development and progression, clinical trials involving EGFR tyrosine kinase inhibitors (TKIs) have yielded poor results in HNSCC patients. Mechanisms of acquired resistance to the EGFR TKI erlotinib was investigated by developing erlotinib-resistant HNSCC cell lines and comparing their gene expression profiles with their parental erlotinib-sensitive HNSCC cell lines using microarray analyses and subsequent pathway and network analyses. Erlotinib-resistant HNSCC cells displayed a significant upregulation in immune response and inflammatory pathways compared to parental cells. Interleukin-6 (IL-6) was one of thirteen genes that was significantly differentially expressed in all erlotinib-resistant HNSCC cell lines, which was validated using RT-PCR and ELISA. Blockade of IL-6 signaling using the IL-6 receptor antagonist tocilizumab, was able to overcome erlotinib-resistance in erlotinib-resistant SQ20B tumors in vivo. Overall, erlotinib-resistant HNSCC cells display elevated IL-6 expression levels compared to erlotinib-sensitive HNSCC cells and blockade of the IL-6 signaling pathway may be an effective strategy to overcome resistance to erlotinib and possibly other EGFR TKIs for HNSCC therapy.
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA. Electronic address: aditya-stanam@uiowa.edu.
authors.forename: Aditya
authors.initials: A
authors.lastname: Stanam
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA. Electronic address: laurie-love-homan@uiowa.edu.
authors.forename: Laurie
authors.initials: L
authors.lastname: Love-Homan
authors.affiliation: Lincoln University of the Commonwealth of Pennsylvania, Lincoln, PA, USA. Electronic address: tisha.joseph@lincoln.edu.
authors.forename: Tisha S
authors.initials: TS
authors.lastname: Joseph
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA; Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA. Electronic address: madelyn-espinosa@uiowa.edu.
authors.forename: Madelyn
authors.initials: M
authors.lastname: Espinosa-Cotton
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA; Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA; Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: andrean-simons@uiowa.edu.
authors.forename: Andrean L
authors.initials: AL
authors.lastname: Simons
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
keywords: EGFR; Erlotinib; HNSCC; IL-6; Resistance; Tocilizumab