title: Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response.
abstract: This study evaluated the preclinical activity and molecular predictors of response to gefitinib (Iressa(R), Astra Zeneca Inc, UK) in nasopharyngeal carcinoma (NPC). The activity of gefitinib was evaluated in four human NPC cell lines--HK1, HONE-1, CNE2, C666-1. A representative gefitinib-sensitive (HK1, IC(50) = 250 nM) and gefitinib-resistant cell line (HONE-1, IC(50) > 15 microM) were selected and compared for expression of epidermal growth factor receptor (EGFR) and related ligands, and activation of downstream proteins. Gefitinib induced G1 cycle arrest, apoptosis and inhibited cell invasion more significantly in HK1 than HONE-1 cells. HK1 expressed higher levels of p-EGFR, lower p-AKT and phospho-signal transducer and activator of transcription 3 (p-STAT3) than other cell lines. EGFR gene was found to be amplified in HK1. Gefitinib at IC(50) concentrations significantly suppressed EGF-induced activation of p-EGFR, phospho-mitogen-activated protein kinase (p-MAPK) and p-STAT3, but p-AKT showed persistent activation in HK1 and HONE-1 cells. There was no difference in EGFR-ligand expression between the 4 NPC cell lines. In NPC samples derived from non-responders to gefitinib, 50% and 60% showed cytoplasmic and nuclear pi-EGFR expression, respectively, and 33% showed p-AKT expression. EGFR or KRAS mutations were not detected. This study suggests that most NPC cell lines are intrinsically resistant to gefitinib (except HK1 cells), and further studies are needed to confirm whether EGFR gene amplification and persistent AKT activation may influence response to gefitinib in NPC.
authors.affiliation: Department of Clinical Oncology, Cancer Drug Testing Unit, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute, Sir YK Pao Centre for Cancer, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. brigette@clo.cuhk.edu.hk
authors.forename: Brigette B Y
authors.initials: BB
authors.lastname: Ma
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.forename: Fan Fong
authors.initials: FF
authors.lastname: Poon
authors.forename: S C Cesar
authors.initials: SC
authors.lastname: Wong
authors.forename: Ka Fai
authors.initials: KF
authors.lastname: To
authors.forename: Elaine
authors.initials: E
authors.lastname: Wong
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
authors.forename: Kwok Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Margaret Heung Ling
authors.initials: MH
authors.lastname: Ng
authors.forename: Suk Hang
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib