Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib

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dc.contributor.authorGiles, K.
dc.contributor.authorKalinowski, F.
dc.contributor.authorCandy, P.
dc.contributor.authorEpis, M.
dc.contributor.authorZhang, P.
dc.contributor.authorRedfern, A.
dc.contributor.authorStuart, L.
dc.contributor.authorGoodall, G.
dc.contributor.authorLeedman, P.
dc.date.issued2013
dc.description.abstractElevated 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.
dc.description.statementofresponsibilityKeith 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
dc.identifier.citationMolecular Cancer Therapeutics, 2013; 12(11):2541-2558
dc.identifier.doi10.1158/1535-7163.MCT-13-0170
dc.identifier.issn1535-7163
dc.identifier.issn1538-8514
dc.identifier.orcidGoodall, G. [0000-0003-1294-0692]
dc.identifier.urihttp://hdl.handle.net/2440/81643
dc.language.isoen
dc.publisherAmer Assoc Cancer Research
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/634375
dc.rights©2013 American Association for Cancer Research
dc.source.urihttps://doi.org/10.1158/1535-7163.mct-13-0170
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectHead and Neck Neoplasms
dc.subjectTriazoles
dc.subjectQuinazolines
dc.subjectBenzocycloheptenes
dc.subjectReceptor Protein-Tyrosine Kinases
dc.subjectProto-Oncogene Proteins
dc.subjectMicroRNAs
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectProtein Kinase Inhibitors
dc.subjectOligonucleotide Array Sequence Analysis
dc.subjectCell Movement
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectDrug Resistance, Neoplasm
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectErlotinib Hydrochloride
dc.subjectAxl Receptor Tyrosine Kinase
dc.titleAxl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib
dc.typeJournal article
pubs.publication-statusPublished

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