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Type: Journal article
Title: Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib
Author: Giles, K.
Kalinowski, F.
Candy, P.
Epis, M.
Zhang, P.
Redfern, A.
Stuart, L.
Goodall, G.
Leedman, P.
Citation: Molecular Cancer Therapeutics, 2013; 12(11):2541-2558
Publisher: Amer Assoc Cancer Research
Issue Date: 2013
ISSN: 1535-7163
Statement of
Keith M. Giles, Felicity C. Kalinowski, Patrick A. Candy, Michael R. Epis, Priscilla M. Zhang, Andrew D. Redfern, Lisa M. Stuart, Gregory J. Goodall and Peter J. Leedman
Abstract: Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (e.g., erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed an HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial-mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated microRNAs (miRNA), and elevated vimentin expression. Phosphorylated receptor tyrosine kinase profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells were blocked with a specific Axl inhibitor, R428, and R428 resensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR = 1.66, P = 0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance.
Keywords: Cell Line, Tumor
Head and Neck Neoplasms
Receptor Protein-Tyrosine Kinases
Proto-Oncogene Proteins
Antineoplastic Combined Chemotherapy Protocols
Protein Kinase Inhibitors
Oligonucleotide Array Sequence Analysis
Cell Movement
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Middle Aged
Erlotinib Hydrochloride
Rights: ©2013 American Association for Cancer Research
DOI: 10.1158/1535-7163.MCT-13-0170
Appears in Collections:Aurora harvest
Molecular and Biomedical Science publications

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