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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hegde, P. S. Articles by Gilmer, T. M. Search for Related Content PubMed PubMed Citation Articles by Hegde, P. S. Articles by Gilmer, T. M.

Research Articles: Therapeutics, Targets, and Development

Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles

Departments of ¹ Genomic and Proteomic Sciences, ² Translational Medicine, and ³ Computational, Analytical, and Structural Sciences, GlaxoSmithKline, Inc., Research Triangle Park, North Carolina

Requests for reprints: Tona M. Gilmer, Department of Translational Medicine, GlaxoSmithKline, Inc., 5 Moore Drive, Research Triangle Park, NC 27709. Phone: 919-483-2100; Fax: 919-315-3749. E-mail: tona.m.gilmer{at}gsk.com

Abstract

Lapatinib (GW572016) is a small-molecule dual inhibitor of epidermal growth factor receptor (ErbB1) and ErbB2 receptor kinase activities currently in phase III clinical trials. We used phosphoprotein and microarray analyses to carry out targeted pathway studies of phosphorylation and gene expression changes in human breast cancer cell lines in the presence or absence of lapatinib. Studies were done in four breast cancer cell lines, two of which were responsive and two of which were nonresponsive to lapatinib. Responsive cell lines, BT474 and SKBr3, constitutively overexpress ErbB2 and show an IC₅₀ of 25 or 32 nmol/L for lapatinib, respectively. In contrast, nonresponsive MDA-MB-468 and T47D cells expressed a low basal level of ErbB2 and showed IC₅₀ values in the micromolar range. Cells responsive to lapatinib exhibited strong differential effects on multiple genes in the AKT pathway. After 12 h of exposure to 1.0 µmol/L of lapatinib, AKT1, MAPK9, HSPCA, IRAK1, and CCND1 transcripts were down-regulated 7- to 25-fold in responsive BT474 and SKBr3 cells. In contrast, lapatinib weakly down-regulated the AKT pathway in nonresponsive breast cancer cell lines (<5-fold down-regulation of most genes in the pathway). Furthermore, the proapoptotic gene FOXO3A, which is negatively regulated by AKT, was up-regulated 7- and 25-fold in lapatinib-responsive SKBr3 and BT474 cells, respectively. Phosphorylated Akt and Akt-mediated phosphorylation of FOXO3A also decreased in responsive breast cancer cell lines exposed to lapatinib. Gene expression profiling also revealed that lapatinib stimulated the expression of estrogen and progesterone receptors and modulated the expression of genes involved in cell cycle control, glycolysis, and fatty acid metabolism. In BT474 and T47D cells, which expressed moderate basal levels of the estrogen and progesterone receptors, 1.0 µmol/L of lapatinib induced expression by 7- to 11-fold. These data provide insight into the mechanism of action of lapatinib in breast cancer cells. [Mol Cancer Ther 2007;6(5):1629–40]

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.

Note: Current address for P.S. Hegde: Department of Development Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080.

⁴ http://www.ebi.ac.uk/arrayexpress/

Received 10/ 3/05; revised 2/21/07; accepted 3/30/07.

This article has been cited by other articles:

				Q. S.C. Chu, M. E. Cianfrocca, L. J. Goldstein, M. Gale, N. Murray, J. Loftiss, N. Arya, K. M. Koch, L. Pandite, R. A. Fleming, et al. A Phase I and Pharmacokinetic Study of Lapatinib in Combination with Letrozole in Patients with Advanced Cancer Clin. Cancer Res., July 15, 2008; 14(14): 4484 - 4490. [Abstract] [Full Text] [PDF]

				A. Vazquez-Martin, C. Oliveras-Ferraros, R. Colomer, J. Brunet, and J. A. Menendez Low-scale phosphoproteome analyses identify the mTOR effector p70 S6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb(R)) in human breast carcinoma cells Ann. Onc., June 1, 2008; 19(6): 1097 - 1109. [Abstract] [Full Text] [PDF]

				T. M. Gilmer, L. Cable, K. Alligood, D. Rusnak, G. Spehar, K. T. Gallagher, E. Woldu, H. L. Carter, A. T. Truesdale, L. Shewchuk, et al. Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib Cancer Res., January 15, 2008; 68(2): 571 - 579. [Abstract] [Full Text] [PDF]