Current approaches and future directions in the treatment of HER2-positive breast cancer.
Current approaches and future directions in the treatment of HER2-positive breast cancer.
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DOI：
10.1016/j.ctrv.2012.04.008
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发表时间：
2013-05
影响因子：
11.8
通讯作者：
Finn, Richard S.
中科院分区：
文献类型：
--
作者：
Hurvitz, Sara A.;Hu, Yufang;O'Brien, Neil;Finn, Richard S.
人表皮生长因子受体2 （HER2）是跨膜受体酪氨酸激酶ErbB家族的一员，在20-30%的浸润性乳腺癌中扩增。HER2扩增与转移和生存率降低有关。两种HER2导向疗法已被美国食品和药物管理局批准用于治疗HER2过表达乳腺癌：曲妥珠单抗，一种针对HER2细胞外部分的人源化单克隆抗体；拉帕替尼，一种HER2和表皮生长因子受体特异性酪氨酸激酶抑制剂。尽管在化疗中加入her2靶向药物可以改善总生存率，但由于固有的耐药性，许多患者不能从这些药物中获益。此外，许多获得初步反应的患者最终获得耐药性。目前，已经描述了几种耐药机制，包括其他信号通路的突变、HER2截断形式的表达、受体串扰和自噬。目前正在研究的几种方法可以靶向这些耐药途径，包括阻断PI3激酶和哺乳动物雷帕霉素信号转导靶点，阻断新生血管生成和血管内皮生长因子轴，使用靶向HER2二聚化位点的单克隆抗体，以及使用HER2单克隆抗体-药物偶联物。在这里，我们将回顾目前这些药物的科学原理，以及这些药物的组合如何产生附加或协同效应，并改善her2扩增乳腺癌患者的预后。
Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20–30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Two HER2-directed therapies have been approved by the United States Food and Drug Administration for the treatment of HER2-overexpressing breast cancer: trastuzumab, a humanized monoclonal antibody against the extracellular portion of HER2; and lapatinib, a dual HER2- and epidermal growth factor receptor-specific tyrosine kinase inhibitor. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance. Currently, several mechanisms of resistance have been described, including mutations in other signaling pathways, expression of a truncated form of HER2, receptor crosstalk, and autophagy. There are several approaches under study to target these pathways of resistance, including blocking PI3 kinase and mammalian target of rapamycin signaling, blocking neoangiogenesis and the vascular endothelial growth factor axis, using monoclonal antibody targeting of the HER2 dimerization site, and using HER2 monoclonal antibody-drug conjugates. Here we will review the current scientific rationale for these agents and how combinations of these agents may yield additive or synergistic effects and lead to improved outcomes for patients with HER2-amplified breast cancer.
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影响因子：
11.2
作者：
Faratian, Dana;Goltsov, Alexey;Harrison, David J.
通讯作者：
Harrison, David J.
磷脂酰肌醇3-激酶过度激活导致拉帕替尼的抗性，这是由mTOR/磷脂酰/磷脂酰肌醇3-激酶抑制剂NVP-BEZ235逆转的。
影响因子：
11.2
作者：
Eichhorn PJ;Gili M;Scaltriti M;Serra V;Guzman M;Nijkamp W;Beijersbergen RL;Valero V;Seoane J;Bernards R;Baselga J
通讯作者：
Baselga J
影响因子：
45.3
作者：
Burstein, Harold J.;Sun, Yan;Badwe, Rajendra
通讯作者：
Badwe, Rajendra
影响因子：
45.3
作者：
Burris, Howard A., III;Rugo, Hope S.;O'Shaughnessy, Joyce A.
通讯作者：
O'Shaughnessy, Joyce A.
影响因子：
11.5
作者：
Blackwell, KL;Dewhirst, MW;Harris, LN
通讯作者：
Harris, LN