Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines.

Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines. Research Abstract Details 

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Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines. Abstract Text:

Wanqing Liu,Xiaolin Wu,Wei Zhang,Raquel C Montenegro,Donna Lee Fackenthal,Jared A Spitz,Lyn Mickley Huff,Federico Innocenti,Soma Das,Edwin H Cook,Nancy J Cox,Susan E Bates,Mark J Ratain,Wanqing Liu,Xiaolin Wu,Wei Zhang,Raquel C Montenegro,Donna Lee Fackenthal,Jared A Spitz,Lyn Mickley Huff,Federico Innocenti,Soma Das,Edwin H Cook,Nancy J Cox,Susan E Bates,Mark J Ratain,Wanqing Liu,Xiaolin Wu,Wei Zhang,Raquel C Montenegro,Donna Lee Fackenthal,Jared A Spitz,Lyn Mickley Huff,Federico Innocenti,Soma Das,Edwin H Cook,Nancy J Cox,Susan E Bates,Mark J Ratain,

PURPOSE: The mechanism of sensitivity and resistance to epidermal growth factor receptor (EGFR) inhibitors is incompletely understood, particularly in cancers other than non-small-cell lung cancer (NSCLC). To understand the variable response to this class of drugs, we used the NCI60 cancer cell lines. We aimed to determine if there are interactions between EGFR expression, mutations, polymorphisms, and gene amplification, and whether these factors are associated with variability in response to EGFR inhibitors. EXPERIMENTAL DESIGN: The EGFRVIII and tyrosine kinase (TK) domain mutations were examined in the NCI60 cancer cell lines. Five polymorphisms, -216G/T, -191C/A, intron 1 (CA)n, R497K, and 2607A/G, were genotyped. EGFR amplification was also assessed with high-density single-nucleotide polymorphism chip and real-time PCR, respectively. The results were correlated with cytotoxicity data for erlotinib and other 11 EGFR inhibitors, as well as other publicly available data for these lines. RESULTS: All 12 inhibitors behaved similarly. No EGFRVIII but putative TK mutations in two cell lines were found. Both mutant cell lines were insensitive to all inhibitors. Meanwhile, response did not correlate with EGFR amplification but with EGFR gene expression, especially in the cell lines with relatively normal gene status. In addition, EGFR expression was associated with the -216G/T polymorphism but not with the intron 1 (CA)n polymorphism. A combination of -216G/T and R497K polymorphisms was weakly associated with drug response. CONCLUSIONS: These observations suggest that in addition to TK mutations, germ-line variability may also contribute to the pharmacodynamics of EGFR inhibitors, particularly when EGFR is genetically normal.

Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines. Publishing Authors By Initials

W Liu,X Wu,W Zhang,RC Montenegro,DL Fackenthal,JA Spitz,LM Huff,F Innocenti,S Das,EH Cook,NJ Cox,SE Bates,MJ Ratain,W Liu,X Wu,W Zhang,RC Montenegro,DL Fackenthal,JA Spitz,LM Huff,F Innocenti,S Das,EH Cook,NJ Cox,SE Bates,MJ Ratain,W Liu,X Wu,W Zhang,RC Montenegro,DL Fackenthal,JA Spitz,LM Huff,F Innocenti,S Das,EH Cook,NJ Cox,SE Bates,MJ Ratain,

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Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Clinical cancer research : an official journal of

VOLUME: 13

Page Numbers: 6788-95

Journal Abbreviation: Clin. Cancer Res.

ISSN: 1078-0432

DAY: 15

MONTH: Nov

YEAR: 2007

Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines. Information

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LANGUAGE: eng

NlmUniqueID: 9502500

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AFFILIATION: Authors' Affiliations: Departments of Medicine and Human Genetics, Committee on Clinical Pharmacology and Pharmacogenomics, and Cancer Research Center, The University of Chicago.

Country: United States

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MEDLINETA: Clin Cancer Res

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