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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®, 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...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Springer US
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953619/ https://www.ncbi.nlm.nih.gov/pubmed/19756373 http://dx.doi.org/10.1007/s10637-009-9316-7 |
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author | 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. |
author_facet | 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. |
author_sort | Ma, Brigette B.Y. |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-009-9316-7) contains supplementary material, which is available to authorized users. |
format | Text |
id | pubmed-2953619 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-29536192010-10-29 Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response 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. Invest New Drugs Preclinical Studies 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-009-9316-7) contains supplementary material, which is available to authorized users. Springer US 2009-09-16 2010-06 /pmc/articles/PMC2953619/ /pubmed/19756373 http://dx.doi.org/10.1007/s10637-009-9316-7 Text en © Springer Science+Business Media, LLC 2009 |
spellingShingle | Preclinical Studies 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. Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response |
title | Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response |
title_full | Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response |
title_fullStr | Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response |
title_full_unstemmed | Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response |
title_short | Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response |
title_sort | preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response |
topic | Preclinical Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953619/ https://www.ncbi.nlm.nih.gov/pubmed/19756373 http://dx.doi.org/10.1007/s10637-009-9316-7 |
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