Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells
Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells
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DOI：
10.1158/0008-5472.can-07-5962
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Sweeney, Colleen
中科院分区：
文献类型：
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作者：
Shattuck, David L.;Miller, Jamie K.;Sweeney, Colleen
Her2 在 20% 至 30% 的乳腺肿瘤中过度表达，并与患者无病生存率和总体生存率降低相关。曲妥珠单抗是一种针对 Her2 的人源化单克隆抗体，代表了第一个 Her2 靶向疗法，可降低复发风险并延长患者生存期。对曲妥珠单抗的耐药性，无论是固有的还是治疗获得性的，都是有效治疗 Her2 (+) 乳腺癌的重大障碍。 Met 受体酪氨酸激酶在乳腺癌中异常表达，预示着患者预后不良。在这项研究中，我们发现 Met 在 Her2 过表达乳腺癌细胞以及 Her2 (+) 乳腺癌细胞中频繁表达。重要的是，Met 有助于曲妥珠单抗耐药性，因为 Met 的抑制使细胞对曲妥珠单抗介导的生长抑制敏感，而 Met 激活则通过消除 p27 诱导来保护细胞免受曲妥珠单抗的侵害。值得注意的是，Her2 过表达的乳腺癌细胞在曲妥珠单抗治疗后迅速上调 Met 表达，从而促进其自身的耐药性。我们的研究表明，Her2 (+) 患者的一部分可能受益于 Her2 和 Met 的联合抑制。
Her2 is overexpressed in 20% to 30% of breast tumors and correlates with reduced disease-free and overall patient survival. Trastuzumab, a humanized monoclonal antibody directed against Her2, represents the first Her2-targeted therapy, which decreases the risk of relapse and prolongs patient survival. Resistance to trastuzumab, both inherent and treatment-acquired, represents a significant barrier to the effective treatment of Her2 (+) breast cancer. The Met receptor tyrosine kinase is aberrantly expressed in breast cancer and predicts poor patient prognosis. In this study, we find that Met is frequently expressed in Her2-overexpressing breast cancer cells, as well as Her2 (+) breast cancer. Importantly, Met contributes to trastuzumab resistance, as inhibition of Met sensitizes cells to trastuzumab-mediated growth inhibition, whereas Met activation protects cells against trastuzumab by abrogating p27 induction. Remarkably, Her2-overexpressing breast cancer cells rapidly up-regulate Met expression after trastuzumab treatment, promoting their own resistance. Our study suggests that a subset of Her2 (+) patients may benefit from combined inhibition of Her2 and Met.