Resistance to Trastuzumab in Breast Cancer.
Resistance to Trastuzumab in Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-09-0636
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发表时间：
2009-12-15
期刊：
影响因子：
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通讯作者：
Mernaugh R
中科院分区：
文献类型：
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作者：
Pohlmann PR;Mayer IA;Mernaugh R
HER 2是一种由HER 2/neu基因编码的跨膜癌蛋白，在大约20%至25%的侵袭性乳腺癌中过表达。它可以通过曲妥珠单抗（一种人源化IgG 1 κ轻链单克隆抗体）进行治疗靶向。尽管曲妥珠单抗目前被认为是肿瘤学中最有效的治疗方法之一，但大量HER 2过表达乳腺癌患者并没有从中受益。因此，了解曲妥珠单抗的作用机制和耐药性对于开发新的治疗策略至关重要。这篇综述讨论了拟议的曲妥珠单抗的作用模式以及拟议的耐药机制。耐药机制分为四个主要类别：（1）阻止曲妥珠单抗与HER 2结合的障碍;（2）上调HER 2下游信号传导途径;（3）通过替代途径进行信号传导;以及（4）未能触发免疫介导的机制来破坏肿瘤细胞。这些可能导致曲妥珠单抗耐药的潜在机制已被用作开发药物的指南，目前正在进行临床试验，以克服耐药。当完全理解曲妥珠单抗耐药的机制时，将为如何最好地治疗HER 2过表达乳腺癌提供见解。因此，了解每种耐药机制对于有针对性地制定克服耐药机制的策略以及开发能够为每种疗法确定和有效选择患者的工具至关重要。
HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20 to 25% of invasive breast cancers. It can be therapeutically targeted by trastuzumab, a humanized IgG1 kappa light chain monoclonal antibody. Although trastuzumab is currently considered one of the most effective treatments in oncology, a significant number of patients with HER2-overexpressing breast cancer do not benefit from it. Understanding the mechanisms of action and resistance to trastuzumab is therefore crucial for the development of new therapeutic strategies. This review discusses proposed trastuzumab mode of action as well as proposed mechanisms for resistance. Mechanisms for resistance are grouped into four main categories: (1) obstacles preventing trastuzumab binding to HER2; (2) upregulation of HER2 downstream signaling pathways; (3) signaling through alternate pathways; and (4) failure to trigger an immune-mediated mechanism to destroy tumor cells. These potential mechanisms through which trastuzumab resistance may arise have been used as a guide to develop drugs, presently in clinical trials, to overcome resistance. The mechanisms conferring trastuzumab resistance, when completely understood, will provide insight on how best to treat HER2-overexpressing breast cancer. The understanding of each mechanism of resistance is therefore critical for the educated development of strategies to overcome it, as well as for the development of tools that would allow definitive and efficient patient selection for each therapy.