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

Brigette B.Y. Ma, Vivian W.Y. Lui, Fan Fong Poon, Sze Chuen Cesar Wong, Ka Fai To, Elaine Wong, Honglin Chen, Kwok Wai Lo, Qian Tao, Anthony T.C. Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

32 Citations (Scopus)

Abstract

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, IC50= 250 nM) and gefitinib-resistant cell line (HONE-1, IC50> 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 IC50concentrations 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.
Original languageEnglish
Pages (from-to)326-333
Number of pages8
JournalInvestigational New Drugs
Volume28
Issue number3
DOIs
Publication statusPublished - 1 Jun 2010
Externally publishedYes

Keywords

  • Epidermal growth factor receptor
  • Gefitinib
  • Head and neck cancer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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