title: Determinants of response to epidermal growth factor receptor tyrosine kinase inhibition in squamous cell carcinoma of the head and neck.
abstract: Dramatic responses to epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors may be seen in non-small cell lung cancers (NSCLCs) with a sensitizing mutation of the EGFR TK domain. It is not known how to predict response in patients with squamous cell carcinoma of the head and neck (SCCHN), where EGFR TK mutations are less frequent and where response rates in unselected patients are disappointing. We have characterized the intrinsic sensitivity of a panel of 18 SCCHN cell lines to gefitinib, an EGFR TK inhibitor, and have investigated correlations between putative markers of response and intrinsic sensitivity. Induction of G1 arrest was only seen in cell lines with GI(50) < 1 microM. Expression of EGFR, by three techniques, correlated with sensitivity to gefitinib. ERB-B2 expression appeared to influence sensitivity to gefitinib but ERB-B3 expression did not. While EGFR tyrosine kinase mutations were not detected, EGFR gene amplification was confirmed by fluorescence in situ hybridization in the most sensitive cell line. The number of cytosine adenine dinucleotide repeats in intron 1 of the EGFR gene did not correlate with sensitivity. E-cadherin expression was detected in cell lines with a range of sensitivities, whereas amphiregulin was secreted predominantly by sensitive cell lines. MET expression was an independent predictor of sensitivity to gefitinib, although neither expression nor phosphorylation of insulin-like growth factor 1 receptor correlated with intrinsic resistance. Breast receptor kinase (BRK) was more highly expressed in the sensitive cell lines, but siRNA knockdown of neither BRK nor MET affected sensitivity. Our data suggest that overexpression of EGFR and multiple related cell surface receptors may be associated with sensitivity to gefitinib and that differences between our data and the literature highlight that biomarkers of response are tumour type- and cell line-dependent.
authors.affiliation: Tumour Biology and Metastasis Team, McElwain Laboratories, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cotswold Road, Sutton, Surrey, SM2 5NG, UK. susanne.rogers@icr.ac.uk
authors.forename: Susanne J
authors.initials: SJ
authors.lastname: Rogers
authors.forename: Carol
authors.initials: C
authors.lastname: Box
authors.forename: Philip
authors.initials: P
authors.lastname: Chambers
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Barbachano
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Nutting
authors.forename: Peter
authors.initials: P
authors.lastname: Rhŷs-Evans
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D000077156:Gefitinib; D015870:Gene Expression; D018734:Genes, erbB-2; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016014:Linear Models; D011110:Polymorphism, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011799:Quinazolines; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib