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首页> 外文期刊>Molecular Cancer >The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells
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The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells

机译：抗-erbB3抗体MM-121 / SAR256212与曲妥珠单抗组合可对抗曲妥珠单抗的乳腺癌细胞产生有效的抗肿瘤活性

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Background Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. Methods MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs’ antitumor activity. Immunohistochemical analyses were carried out to study the Abs’ inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo . Results MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor tissues. Conclusions The combination of MM-121 and trastuzumab not only inhibits erbB2-overexpressing breast cancer cell proliferation, but also promotes the otherwise trastuzumab-resistant cells undergoing apoptosis in an in vivo xenografts model. Thus, MM-121 exhibits potent antitumor activity when combined with trastuzumab under the studied conditions. Our data suggest that further studies regarding the suitability of MM-121 for treatment of breast cancer patients whose tumors overexpress erbB2 and become resistant to trastuzumab may be warranted.
机译：背景技术据报道，erbB3受体的表达升高会诱导对包括trabuz2在内的erbB2乳腺癌的治疗药物产生抗药性。我们最近的研究表明，erbB3与erbB2和IGF-1受体相互作用，在抗曲妥珠单抗的乳腺癌细胞中形成异源三聚体复合物。在这里，我们调查了MM-121 / SAR256212（一种完全的人类抗erbB3抗体（Ab））对两种对曲妥珠单抗具有抗性的erbB2过表达的乳腺癌细胞系的抗肿瘤活性。方法采用基于MTS的增殖测定法测定曲妥珠单抗和/或MM-121 / SAR256212处理后的细胞活力。通过流式细胞术分析检查细胞周期进程。进行蛋白质印迹分析以确定蛋白质的表达和活化。通过将抗曲妥珠单抗的BT474-HR20细胞接种到裸鼠中来建立肿瘤异种移植物。通过腹腔注射曲妥珠单抗和/或MM-121 / SAR256212处理荷瘤小鼠，以确定Abs的抗肿瘤活性。进行了免疫组织化学分析，研究了Abs在体内对肿瘤细胞增殖和凋亡诱导的抑制作用。结果MM-121显着增强了曲妥珠单抗对两种敏感和两种耐药乳腺癌细胞系的生长抑制作用。在体外研究中，MM-121与曲妥珠单抗组合导致磷酸化的erbB3（P-erbB3）和Akt（P-Akt）显着降低。 MM-121联合曲妥珠单抗在我们的细胞培养条件下不会诱导曲妥珠单抗耐药细胞株的凋亡，而是诱导细胞周期G1阻滞，这主要与p27 kip1 < / sup>。有趣的是，在由曲妥珠单抗耐药细胞建立的肿瘤异种移植模型中，与单独使用两种药物相比，MM-121与曲妥珠单抗联合使用显着抑制了肿瘤的生长，并显着降低了Ki67染色并降低了裂解的caspase-3组织。结论MM-121和曲妥珠单抗的组合不仅抑制过表达erbB2的乳腺癌细胞增殖，而且在体内异种移植模型中促进原本抗曲妥珠单抗的细胞凋亡。因此，当在研究条件下与曲妥珠单抗组合使用时，MM-121表现出有效的抗肿瘤活性。我们的数据表明，可能需要对MM-121的治疗是否适合乳腺癌患者进行研究，这些患者的肿瘤过表达erbB2并对曲妥珠单抗产生耐药性。

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