Konecny Gottfried E, Pegram Mark D, Venkatesan Natarajan, Finn Richard, Yang Guorong, Rahmeh Martina, Untch Michael, Rusnak David W, Spehar Glenn, Mullin Robert J, Keith Barry R, Gilmer Tona M, Berger Mark, Podratz Karl C, Slamon Dennis J
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 12-145 Factor Building, 10945 Le Conte Avenue, Los Angeles, CA 90095-1678, USA.
Cancer Res. 2006 Feb 1;66(3):1630-9. doi: 10.1158/0008-5472.CAN-05-1182.
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 IC(50)s (range, 0.010-18.6 micromol/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 microg/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.
拉帕替尼（GW572016）是一种表皮生长因子受体（EGFR）和HER-2酪氨酸激酶的选择性抑制剂。在此，我们通过检测拉帕替尼对31种特征明确的人乳腺癌细胞系（包括曲妥珠单抗处理过的HER-2阳性细胞系）中肿瘤细胞生长的影响，来探索其治疗潜力。我们进一步表征其与曲妥珠单抗联合使用时的活性，并分析EGFR和HER-2的表达或EGFR、HER-2、Raf、AKT或细胞外信号调节激酶（ERK）激活中诱导的变化是否为药物活性的标志物。我们报告称，在所有测试的乳腺癌细胞系中均观察到拉帕替尼浓度依赖性的抗增殖作用，但各细胞系之间差异显著，IC50值相差高达1000倍（范围为0.010 - 18.6 μmol/L）。对拉帕替尼的反应与HER-2表达及其抑制HER-2、Raf、AKT和ERK磷酸化的能力显著相关。在无胸腺小鼠中用人乳腺癌异种移植瘤进行了拉帕替尼的长期体内研究。与未治疗的对照组相比，77天的治疗导致异种移植瘤体积持续且显著减小。对于拉帕替尼加曲妥珠单抗的联合用药，在四种不同的HER-2过表达细胞系中观察到协同药物相互作用。此外，拉帕替尼对在含曲妥珠单抗（100 μg/mL）培养基中选择进行长期传代培养（>9个月）的细胞系仍具有显著的体外活性。这些观察结果为在HER-2过表达乳腺癌以及对曲妥珠单抗临床耐药的患者中测试拉帕替尼作为单一药物或与曲妥珠单抗联合使用提供了明确的生物学依据。
