title: Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition.
abstract: Inhibition of epidermal growth factor receptor (EGFR) signalling has emerged as a new treatment strategy for oral squamous cell carcinoma (OSCC). Previously, we found that loss of EGFR expression in OSCC was associated with epithelial-mesenchymal transition (EMT), and may have functional implications with regard to resistance to cetuximab, a monoclonal anti-EGFR antibody. Eribulin (a microtubule inhibitor) reportedly renders breast cancer less aggressive, and less likely to metastasise, by triggering mesenchymal‑to‑epithelial (MET) transition. In the present study we evaluated whether eribulin-induced MET was associated with re-sensitization of resistant OSCC cell lines to cetuximab. In vitro antiproliferative activities were determined in three human OSCC lines (OSC-20, OSC-19 and HOC313) treated with eribulin. These three human OSCC represented different EMT/MET states. Interestingly, HOC313 cells (mesenchymal phenotype) were highly sensitive to eribulin in comparison with other cell lines, and significantly enhanced the anti-proliferative effect of cetuximab in response to the drug. Eribulin also underwent a MET-associated gene switch that resulted in morphological changes and high EGFR expression in HOC313 cells, and abrogated a TGF-β-induced EMT gene expression signature. Eribulin-dependent sensitization of OSCC to cetuximab is likely due to induction of MET. Combination therapies based on eribulin and cetuximab have potential as a novel treatment regimen in OSCC.
authors: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.
authors: Hiroko
authors: H
authors: Kitahara
authors: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.
authors: Mariko
authors: M
authors: Hirai
authors: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.
authors: Koroku
authors: K
authors: Kato
authors: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool L7 8TX, UK.
authors: George
authors: G
authors: Bou-Gharios
authors: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.
authors: Hiroyuki
authors: H
authors: Nakamura
authors: Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.
authors: Shuichi
authors: S
authors: Kawashiri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015854:Up-Regulation; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D005663:Furans; D007659:Ketones; C512478:EGFR protein, human; C490954:eribulin; D000095662:Polyether Polyketides