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

TitlePreclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response
Authors
KeywordsEpidermal growth factor receptor
Gefitinib
Head and neck cancer
Issue Date2010
PublisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-6997
Citation
Investigational New Drugs, 2010, v. 28 n. 3, p. 326-333 How to Cite?
AbstractThis 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, 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 IC50 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. © 2009 Springer Science+Business Media, LLC.
Persistent Identifierhttp://hdl.handle.net/10722/124032
ISSN
2015 Impact Factor: 3.281
2015 SCImago Journal Rankings: 1.376
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council Competitive Earmarked Research Grant4445/05M
Funding Information:

This study was supported by the Research Grant Council Competitive Earmarked Research Grant (Reference 4445/05M). Result of this study was presented in part at the Annual Meeting of the American Association of Clinical Oncology 2007, abstract 3171, April 14-18, 2007, Los Angeles, CA. We thank Astra Zeneca Inc for providing gefitinib in this study.

References

 

DC FieldValueLanguage
dc.contributor.authorMa, BBYen_HK
dc.contributor.authorLui, VWYen_HK
dc.contributor.authorPoon, FFen_HK
dc.contributor.authorWong, SCCen_HK
dc.contributor.authorTo, KFen_HK
dc.contributor.authorWong, Een_HK
dc.contributor.authorChen, Hen_HK
dc.contributor.authorLo, KWen_HK
dc.contributor.authorTao, Qen_HK
dc.contributor.authorChan, ATCen_HK
dc.date.accessioned2010-10-19T04:34:34Z-
dc.date.available2010-10-19T04:34:34Z-
dc.date.issued2010en_HK
dc.identifier.citationInvestigational New Drugs, 2010, v. 28 n. 3, p. 326-333en_HK
dc.identifier.issn0167-6997en_HK
dc.identifier.urihttp://hdl.handle.net/10722/124032-
dc.description.abstractThis 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, 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 IC50 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. © 2009 Springer Science+Business Media, LLC.en_HK
dc.languageengen_HK
dc.publisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0167-6997en_HK
dc.relation.ispartofInvestigational New Drugsen_HK
dc.rightsSpringer Science+Business Media, LLCen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectEpidermal growth factor receptoren_HK
dc.subjectGefitiniben_HK
dc.subjectHead and neck canceren_HK
dc.titlePreclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of responseen_HK
dc.typeArticleen_HK
dc.identifier.emailChen, H:hlchen@hkucc.hku.hken_HK
dc.identifier.authorityChen, H=rp00383en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1007/s10637-009-9316-7en_HK
dc.identifier.pmid19756373-
dc.identifier.pmcidPMC2953619-
dc.identifier.scopuseid_2-s2.0-77952242739en_HK
dc.identifier.hkuros180691-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77952242739&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume28en_HK
dc.identifier.issue3en_HK
dc.identifier.spage326en_HK
dc.identifier.epage333en_HK
dc.identifier.eissn1573-0646en_HK
dc.identifier.isiWOS:000276430200015-
dc.publisher.placeUnited Statesen_HK
dc.description.otherSpringer Open Choice, 01 Dec 2010-
dc.identifier.scopusauthoridMa, BBY=7403301016en_HK
dc.identifier.scopusauthoridLui, VWY=7004231347en_HK
dc.identifier.scopusauthoridPoon, FF=24577252600en_HK
dc.identifier.scopusauthoridWong, SCC=26039647800en_HK
dc.identifier.scopusauthoridTo, KF=7101911940en_HK
dc.identifier.scopusauthoridWong, E=8234468400en_HK
dc.identifier.scopusauthoridChen, H=26643315400en_HK
dc.identifier.scopusauthoridLo, KW=7402101603en_HK
dc.identifier.scopusauthoridTao, Q=7102578359en_HK
dc.identifier.scopusauthoridChan, ATC=13404833700en_HK
dc.identifier.citeulike5815644-

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