Department of Gynecology and Obstetrics, University of Regensburg, Germany.
Cytometry A. 2011 Sep;79(9):684-93. doi: 10.1002/cyto.a.21107. Epub 2011 Jul 22.
Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor- and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRG-caused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting.
在过去的十年中，许多单克隆抗体和小分子抑制剂已成为治疗 Her2/neu 过表达乳腺癌的有效治疗药物。然而，许多患者并未充分响应针对表皮生长因子受体 (EGFR)/Her2 受体的靶向治疗。受体及其生长刺激作用，可能会阻碍抗增殖细胞治疗，目前几乎没有进行研究。BT474 和 SK-BR-3 乳腺癌细胞系分别用曲妥珠单抗、帕妥珠单抗和拉帕替尼单独治疗，采用不同的组合和浓度。此外，还添加了表皮生长因子 (EGF) 或人表皮生长因子 (HRG)，以揭示潜在的生长因子介导的补偿作用。分析了受体和细胞内信号传导作为细胞处理的功能。读出参数为细胞增殖和细胞凋亡。曲妥珠单抗可有效诱导 BT474 细胞静止，但帕妥珠单抗治疗无效。然而，同时给予 EGF 或 HRG 可恢复 BT474 细胞的增殖能力。相比之下，两种治疗性抗体处理均未导致 SK-BR-3 细胞周期进展的明显抑制。拉帕替尼是两种细胞系中最有效的细胞周期抑制剂，尽管在存在 EGF 和 HRG 的情况下，其作用显著减弱。曲妥珠单抗和帕妥珠单抗治疗也逆转了 EGF 对拉帕替尼诱导的细胞周期抑制的补偿作用。最重要的是，HRG 引起的拉帕替尼诱导的细胞周期退出补偿作用被帕妥珠单抗逆转，而不是被曲妥珠单抗逆转。显然，使用曲妥珠单抗、帕妥珠单抗和拉帕替尼进行多种抗 EGFR/Her2 靶向治疗更有效地影响受体功能（相互作用和激活），从而增强其抗增殖能力。然而，针对 Her/ErbB 受体的抗癌药物的生长抑制作用在存在 EGF 尤其是 HRG 处理的情况下会受到严重破坏，这表明特定的治疗性生长因子隔离可能会进一步增强抗 EGFR/Her2 靶向作用。
