Shattuck David L, Miller Jamie K, Carraway Kermit L, Sweeney Colleen
University of California Davis Cancer Center, Sacramento, CA 95817, USA.
Cancer Res. 2008 Mar 1;68(5):1471-7. doi: 10.1158/0008-5472.CAN-07-5962.
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.
Her2在20%至30%的乳腺肿瘤中过度表达，与无病生存期缩短和患者总生存期相关。曲妥珠单抗是一种针对Her2的人源化单克隆抗体，是第一种Her2靶向治疗药物，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，包括固有耐药性和治疗获得性耐药性，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，预示患者预后不良。在本研究中，我们发现Met在Her2过表达的乳腺癌细胞以及Her2（+）乳腺癌中频繁表达。重要的是，Met导致曲妥珠单抗耐药，因为抑制Met可使细胞对曲妥珠单抗介导的生长抑制敏感，而激活Met则通过消除p27诱导来保护细胞免受曲妥珠单抗的影响。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，从而促进自身耐药。我们的研究表明，一部分Her2（+）患者可能受益于Her2和Met的联合抑制。
