The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells.
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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抗 erbB3 抗体 MM-121/SAR256212 与曲妥珠单抗联合使用，可对曲妥珠单抗耐药的乳腺癌细胞发挥有效的抗肿瘤活性。
DOI：
10.1186/1476-4598-12-134
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发表时间：
2013-11-11
期刊：
影响因子：
37.3
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Huang J;Wang S;Lyu H;Cai B;Yang X;Wang J;Liu B
据报道，erbB3受体的高表达会导致对包括曲妥珠单抗在内的治疗药物的耐药，导致erbB2过表达的乳腺癌。我们最近的研究表明，在曲妥珠单抗耐药的乳腺癌细胞中，erbB3与erbB2和IGF-1受体相互作用，形成异源三聚体复合体。在这里，我们研究了MM-121/SAR256212，一种完全人源性的抗erbB3抗体(Ab)，对两种对曲妥珠单抗耐药的过表达的乳腺癌细胞株的抗肿瘤活性。用MTS法检测曲妥珠单抗和/或MM-121/SAR256212作用后的细胞存活率。流式细胞仪检测细胞周期进程。Western印迹分析确定蛋白质的表达和活化。将耐曲妥珠单抗的BT474-HR20细胞接种于裸鼠体内，建立肿瘤移植瘤模型。用曲妥珠单抗和/或MM-121/SAR256212对荷瘤小鼠进行腹腔注射，检测其抗肿瘤活性。采用免疫组织化学方法研究抗体在体内对肿瘤细胞增殖的抑制作用和对细胞凋亡的诱导作用。MM-121显著增强曲妥珠单抗对两种敏感和两种耐药乳腺癌细胞的生长抑制作用。在体外研究中，MM-121与曲妥珠单抗联合应用可显著降低磷酸化的erbB3(P-erbB3)和Akt(P-Akt)。在我们的细胞培养条件下，MM-121联合曲妥珠单抗不能诱导曲妥珠单抗耐药细胞株的凋亡，而是诱导细胞周期G1期停滞，主要与p27kip1上调有关。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，MM-121联合曲妥珠单抗与单独使用曲妥珠单抗相比显著抑制肿瘤生长，与显著减少Ki67染色和增加肿瘤组织中切割的caspase-3有关。MM-121与曲妥珠单抗联合应用不仅能抑制过表达erbB2的乳腺癌细胞的增殖，还能在体内异种移植模型中促进耐曲妥珠单抗的细胞发生凋亡。因此，在所研究的条件下，MM-121与曲妥珠单抗联合使用时显示出很强的抗肿瘤活性。我们的数据表明，关于MM-121是否适合治疗肿瘤过度表达erbB2并对曲妥珠单抗产生抗药性的乳腺癌患者的进一步研究可能是有必要的。
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. 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. 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. 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.
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影响因子：
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作者：
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影响因子：
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