Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer.
Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer.
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DOI：
10.5402/2012/428062
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Nahta R
中科院分区：
文献类型：
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作者：
Nahta R
过去十年对HER2过表达乳腺癌的研究为HER2信号驱动肿瘤进展的机制以及癌细胞逃避HER2靶向治疗的抗癌活性的潜在机制提供了重要的见解。许多这些临床前研究结果已转化为临床开发，导致her2靶向治疗的新组合以及曲妥珠单抗加耐药途径抑制剂的组合。在本文中，我们将讨论曲妥珠单抗耐药的机制，包括表位掩蔽、来自其他细胞表面受体的交叉信号传导、过度活跃的下游信号传导以及诱导抗体依赖性细胞毒性的失败。此外，我们将讨论双重HER2抑制作用的分子机制，特别是曲妥珠单抗联合拉帕替尼或曲妥珠单抗联合帕妥珠单抗。我们还将讨论支持曲妥珠单抗与靶向曲妥珠单抗耐药分子的药物联合治疗的数据。胰岛素样生长因子- 1受体和雌激素受体在her2靶向治疗耐药的背景下的作用进行了讨论。最后，我们将研究需要解决的主要问题，以便将这些组合从实验室转化为临床，包括需要建立相关的生物标志物，以选择那些最有可能从特定药物组合中受益的患者。
The past decade of research into HER2-overexpressing breast cancer has provided significant insight into the mechanisms by which HER2 signaling drives tumor progression, as well as potential mechanisms by which cancer cells escape the anticancer activity of HER2-targeted therapy. Many of these preclinical findings have been translated into clinical development, resulting in novel combinations of HER2-targeted therapies and combinations of trastuzumab plus inhibitors of resistance pathways. In this paper, we will discuss proposed mechanisms of trastuzumab resistance, including epitope masking, cross signaling from other cell surface receptors, hyperactive downstream signaling, and failure to induce antibody-dependent cellular cytotoxicity. In addition, we will discuss the molecular mechanisms of action of dual HER2 inhibition, specifically the combination of trastuzumab plus lapatinib or trastuzumab with pertuzumab. We will also discuss data supporting therapeutic combinations of trastuzumab with agents targeted against molecules implicated in trastuzumab resistance. The roles of insulin-like growth factor-I receptor and the estrogen receptor are discussed in the context of resistance to HER2-targeted therapies. Finally, we will examine the major issues that need to be addressed in order to translate these combinations from the bench to the clinic, including the need to establish relevant biomarkers to select for those patients who are most likely to benefit from a particular drug combination.