Microarray gene expression studies to discover novel determinants of sensitivity to gefitinib in squamous cell carcinoma of the head and neck

4849 EGFR is a compelling molecular target in squamous cell carcinoma of the head and neck (SCCHN). EGFR overexpression correlates with aggressive disease and poor patient survival. EGFR inhibition can improve survival in conjunction with radiotherapy, but as a minority of patients respond to single agent EGFR inhibitors, predictive markers of response are keenly sought. We performed genome-wide expression cDNA microarrays to discover novel determinants of sensitivity to gefitinib, an EGFR tyrosine kinase inhibitor (TKI).
 3 sensitive (GI 50 50 >10.9 μM) were selected from a panel of 18 cell lines previously characterised by a sulphorhodamine B cell proliferation assay . RNA from at least 3 biological repeats of each cell line was hybridised to 30K cDNA arrays (Cancer Research UK DNA microarray facility). Image processing was performed using GenePix Pro 6.0 (Molecular Devices) and files were analysed using Genespring (Agilent Technologies). Ingenuity Pathway Analysis (Ingenuity® systems) software was used to derive pathway information.
 1038 genes were differentially expressed between the sensitive and resistant cell lines (Welch t-test; FDR 5%). This data confirmed our previous findings at the protein level that contrast with the published literature: E-cadherin expression is not differentially expressed between gefitinib-sensitive and -resistant SCCHN cell lines, and MET and amphiregulin expression are greater in sensitive than resistant cell lines. 18 genes of interest (p 4 and its substrate laminin 5, and demonstrated increased cell adhesion in gefitinib-sensitive cell lines. The expression of both integrin β 4 and P-cadherin are predictive of sensitivity in previously uncharacterised SCCHN cell lines. These markers may be of value in achieving our aim of identifying predictive markers of response to EGFR TKIs and, ultimately, personalising cancer therapy.