Barbacci E Gabriella, Pustilnik Leslie R, Rossi Ann Marie K, Emerson Erling, Miller Penny E, Boscoe Brian P, Cox Eric D, Iwata Kenneth K, Jani Jitesh P, Provoncha Kathleen, Kath John C, Liu Zhengyu, Moyer James D
Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.
Cancer Res. 2003 Aug 1;63(15):4450-9.
Aberrant expression or activity of epidermal growth factor receptor (EGFr) or the closely related p185(erbB2) can promote cell proliferation and survival and thereby contribute to tumorigenesis. Specific antibodies and low molecular-weight tyrosine kinase inhibitors of both proteins are in clinical trials for cancer treatment. CP-654577 is a potent inhibitor selective for p185(erbB2), relative to EGFr tyrosine kinase, and selectively reduces erbB2 autophosphorylation in intact cells. Treatment of SKBr3 human breast cancer cells with CP-654577 reduces the levels of the activated form of mitogen-activated protein kinase, increases the levels of cyclin-dependent kinase inhibitor p27(kip1) and reduces expression of cyclins D and E. These biochemical changes result in a reduced level of phosphorylated retinoblastoma protein and an inhibition of cell-cycle progression at G(1). Apoptosis is triggered in both SKBr3 and another high erbB2-expressing cell line, BT474, by exposure to 1 micro M CP-654577, but this effect is not observed in MCF7 cells that express low erbB2. Levels of activated Akt, an important positive regulator of cell survival, are reduced within 2 h of exposure to 250 nM CP-654577, and this may contribute to the increased apoptosis. These biochemical effects are distinct from those produced by Tarceva, a selective EGFr inhibitor. The antitumor activity of CP-654577 was investigated in athymic mice bearing s.c. tumors from Fischer rat embryo fibroblasts transfected with erbB2. CP-654577 produced a dose-dependent reduction of p185(erbB2) autophosphorylation and inhibited the growth of these tumors. CP-654577 warrants further evaluation in tumors with high expression of p185(erbB2) and may differ from selective EGFr inhibitors or nonselective dual EGFr/erbB2 inhibitors in efficacy and therapeutic index.
表皮生长因子受体（EGFr）或与之密切相关的p185（erbB2）的异常表达或活性可促进细胞增殖和存活，进而导致肿瘤发生。这两种蛋白的特异性抗体和低分子量酪氨酸激酶抑制剂正处于癌症治疗的临床试验阶段。相对于EGFr酪氨酸激酶，CP - 654577是一种对p185（erbB2）有选择性的强效抑制剂，并且能在完整细胞中选择性降低erbB2自身磷酸化水平。用CP - 654577处理SKBr3人乳腺癌细胞可降低丝裂原活化蛋白激酶活化形式的水平，增加细胞周期蛋白依赖性激酶抑制剂p27（kip1）的水平，并降低细胞周期蛋白D和E的表达。这些生化变化导致视网膜母细胞瘤蛋白磷酸化水平降低，并在G（1）期抑制细胞周期进程。通过暴露于1μM CP - 654577，SKBr3和另一种高表达erbB2的细胞系BT474中均触发了凋亡，但在低表达erbB2的MCF7细胞中未观察到这种效应。细胞存活的重要正向调节因子活化型Akt的水平在暴露于250 nM CP - 654577后2小时内降低，这可能导致凋亡增加。这些生化效应与选择性EGFr抑制剂Tarceva所产生的效应不同。在携带经erbB2转染的Fischer大鼠胚胎成纤维细胞皮下肿瘤的无胸腺小鼠中研究了CP - 654577的抗肿瘤活性。CP - 654577使p185（erbB2）自身磷酸化呈剂量依赖性降低，并抑制这些肿瘤的生长。CP - 654577值得在高表达p185（erbB2）的肿瘤中进一步评估，并且在疗效和治疗指数方面可能与选择性EGFr抑制剂或非选择性双EGFr/erbB2抑制剂不同。
