Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response.
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.
Ma
Brigette B Y
BB
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
Lui
Vivian W Y
VW
Poon
Fan Fong
FF
Wong
S C Cesar
SC
To
Ka Fai
KF
Wong
Elaine
E
Chen
Honglin
H
Lo
Kwok Wai
KW
Tao
Qian
Q
Chan
Anthony T C
AT
Ng
Margaret Heung Ling
MH
Cheng
Suk Hang
SH
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
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