This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Greshock, J. Articles by Zaks, T. PubMed PubMed Citation Articles by Greshock, J. Articles by Zaks, T.

Research Articles: Therapeutics, Targets, and Development

Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines

¹ Translational Medicine Oncology, GlaxoSmithKline, King of Prussia, Pennsylvania and ² Department of Biostatistics and Data Management and ³ Medicines Development Center, Oncology, GlaxoSmithKline, Collegeville, Pennsylvania

Requests for reprints: Tal Z. Zaks, Translational Medicine Oncology, GlaxoSmithKline, 1250 South Collegeville Road, UP 4W-4230, Collegeville, PA 19426. Phone: 610-917-5124; Fax: 610-917-4830. E-mail: Tal.Z.Zaks{at}gsk.com

Abstract

A common aim of pharmacogenomic studies that use genome-wide assays on panels of cancers is the unbiased discovery of genomic alterations that are associated with clinical outcome and drug response. Previous studies of lapatinib, a selective dual-kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2 tyrosine kinases, have shown predictable relationships between the activity of these target genes and response. Under the hypothesis that additional genes may play a role in drug sensitivity, a predictive model for lapatinib response was constructed from genome-wide DNA copy number data from 24 cancer cell lines. An optimal predictive model which consists of aberrations at nine distinct genetic loci, includes gains of HER2, EGFR, and loss of CDKN2A. This model achieved an area under the receiver operating characteristic curve of 0.85 (80% confidence interval, 0.70–0.98; P < 0.01), and correctly classified the sensitivity status of 8 of 10 head and neck cancer cell lines. This study shows that biomarkers predictive for lapatinib sensitivity, including the previously described copy number gains of EGFR and HER2, can be discovered using novel genomic assays in an unbiased manner. Furthermore, these results show the utility of DNA copy number profiles in pharmacogenomic studies. [Mol Cancer Ther 2008;7(4):935–43]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/18/07; revised 12/19/07; accepted 1/10/08.