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[Cancer Research 66, 1630-1639, February 1, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Activity of the Dual Kinase Inhibitor Lapatinib (GW572016) against HER-2-Overexpressing and Trastuzumab-Treated Breast Cancer Cells

Gottfried E. Konecny1,2, Mark D. Pegram1, Natarajan Venkatesan1, Richard Finn1, Guorong Yang1, Martina Rahmeh3, Michael Untch3, David W. Rusnak4, Glenn Spehar4, Robert J. Mullin5, Barry R. Keith4, Tona M. Gilmer4, Mark Berger6, Karl C. Podratz2 and Dennis J. Slamon1

1 Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles and Jonsson Comprehensive Cancer Center, Los Angeles, California; 2 Department of Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota; 3 Department of Obstetrics and Gynecology, Klinikum Grosshadern, Ludwig Maximilians Universität München, Munich, Germany; 4 GlaxoSmithKline, Research Triangle Park, North Carolina; 5 Piedmont Research Center, Morrisville, North Carolina; and 6 GlaxoSmithKline, Collegeville, Pennsylvania

Requests for reprints: Gottfried E. Konecny, Division of Hematology-Oncology, University of California at Los Angeles, 12-145 Factor Building, 10945 Le Conte Avenue, Los Angeles, CA 90095-1678. E-mail: gkonecny{at}ucla.edu.

Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC50s (range, 0.010-18.6 µmol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (>9 months) in trastuzumab-containing (100 µg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab. (Cancer Res 2006; 66(3): 1630-9)




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