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

Authors' Affiliations: Departments of ¹ Medicine and ² Human Genetics, ³ Committee on Clinical Pharmacology and Pharmacogenomics, and ⁴ Cancer Research Center, The University of Chicago; ⁵ Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois; and ⁶ Cancer Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Mark J. Ratain, The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637. Phone: 773-702-4400; Fax: 773-702-3969; E-mail: mratain{at}medicine.bsd.uchicago.edu.

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.

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