Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance.
Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance.
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DOI：
10.2174/092986712799320691
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发表时间：
2012
影响因子：
4.1
通讯作者：
Nahta R
中科院分区：
文献类型：
--
作者：
Nahta R
大约20-30%的乳腺癌显示HER2受体酪氨酸激酶的表达增加。曲妥珠单抗（赫赛汀）是一种临床批准的抗her2单克隆抗体。许多her2过表达的转移性乳腺癌患者对曲妥珠单抗有反应；然而，一小部分表现为原发性耐药。此外，许多最初对曲妥珠单抗有反应的患者最终会发展为疾病进展。文献中提出了导致曲妥珠单抗耐药的多种分子机制。这些机制包括来自相关HER/erbB受体的交叉信号和来自HER/erbB家族外受体的代偿信号，包括胰岛素样生长因子- 1、血管内皮生长因子和转化生长因子β的受体。HER2串扰激活的主要下游信号通路是PI3K/mTOR，受体串扰的潜在整合子是Src-focal adhesion kinase （FAK）信号。PI3K、Src和FAK分别与曲妥珠单抗耐药有关。在这篇综述中，我们将讨论HER2串扰的药理学抑制作为治疗曲妥珠单抗难治性HER2过表达乳腺癌的策略。
Approximately 20–30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor crosstalk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.
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