Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response

• Published in: Investigational new drugs Vol. 28; no. 3; pp. 326 - 333
• Main Authors: Ma, Brigette B.Y., Lui, Vivian W.Y., Poon, Fan Fong, Wong, S.C. Cesar, To, Ka Fai, Wong, Elaine, Chen, Honglin, Lo, Kwok Wai, Tao, Qian, Chan, Anthony T.C.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-06-2010; Springer Nature B.V
• Subjects: Antibodies; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Biomarkers; Biomarkers, Pharmacological - metabolism; Biopsy; Cancer; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular biology; Chemotherapy; DNA Mutational Analysis - methods; Drug Resistance, Neoplasm - genetics; Drug Screening Assays, Antitumor; Epidermal growth factor; Gene amplification; Gene Expression Regulation, Neoplastic - drug effects; Head & neck cancer; Humans; Kinases; Laboratories; Ligands; Medicine; Medicine & Public Health; Mutation; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - metabolism; Neoplasm Invasiveness - prevention & control; Oncology; Pharmacology; Pharmacology/Toxicology; Preclinical Studies; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); Quinazolines - pharmacology; Quinazolines - therapeutic use; ras Proteins - genetics; Receptor, Epidermal Growth Factor - genetics; Software; Gefitinib; Head and neck cancer; Epidermal growth factor receptor
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-009-9316-7

Summary
This study evaluated the preclinical activity and molecular predictors of response to gefitinib (Iressa®, 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 μM) 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.