Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA).

Content Provider	Europe PMC
Author	Kokubo, Y Gemma, A Noro, R Seike, M Kataoka, K Matsuda, K Okano, T Minegishi, Y Yoshimura, A Shibuya, M Kudoh, S
Copyright Year	2005
Abstract	Gefitinib (IRESSA), an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor, has antitumour activity in the advanced non-small-cell lung cancer (NSCLC) setting. However, in chemotherapy-naïve patients with advanced NSCLC, the addition of gefitinib to standard chemotherapy regimens failed to increase survival. These results suggest the need for improved patient selection and combination rationales for targeted therapies. We have identified subpopulations of an adenocarcinoma cell line that are naturally resistant to gefitinib, and have analysed the cDNA expression profiles, genomic status of EGFR gene and the effect of gefitinib on signalling pathways in these cell lines in order to identify key mechanisms for naturally acquired resistance to gefitinib. Gefitinib-resistant subpopulations demonstrated increased Akt phosphorylation (not inhibited by gefitinib), reduced PTEN protein expression and loss of the EGFR gene mutation when compared with parental cell lines. These differences in Akt and PTEN protein expression were not evident from the cDNA array profiles. These data suggests that (1) the EGFR gene mutation may be possibly lost in some cancer cells with other additional mechanisms for activating Akt, (2) reintroduction of PTEN or pharmacological downregulation of the constitutive PI3K–Akt-pathway activity may be an attractive therapeutic strategy in cancers with gefitinib resistance.
ISSN	00070920
Journal	British Journal of Cancer
Volume Number	92
PubMed Central reference number	PMC2362053
Issue Number	9
PubMed reference number	15870831
e-ISSN	15321827
DOI	10.1038/sj.bjc.6602559
Language	English
Publisher	Nature Publishing Group
Publisher Date	2005-05-01
Access Restriction	Open
Rights License	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. Copyright © 2005 Cancer Research UK
Subject Keyword	gefitinib PTEN Akt epidermal growth factor receptor(EGFR) gene mutation natural resistance
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology