Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/81643
Citations
Scopus Web of Science® Altmetric
?
?
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
1538-8514
Statement of
Responsibility: 
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; Humans; Head and Neck Neoplasms; Triazoles; Quinazolines; Benzocycloheptenes; Receptor Protein-Tyrosine Kinases; Proto-Oncogene Proteins; MicroRNAs; Antineoplastic Combined Chemotherapy Protocols; Protein Kinase Inhibitors; Oligonucleotide Array Sequence Analysis; Cell Movement; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Adult; Aged; Middle Aged; Female; Male; Erlotinib Hydrochloride
Rights: ©2013 American Association for Cancer Research
RMID: 0020132991
DOI: 10.1158/1535-7163.MCT-13-0170
Appears in Collections:Molecular and Biomedical Science publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.