The root cause of drug resistance in HER2-positive breast cancer and the therapeutic approaches to overcoming the resistance.
The root cause of drug resistance in HER2-positive breast cancer and the therapeutic approaches to overcoming the resistance.
复制标题
HER2阳性乳腺癌中耐药性的根本原因以及克服耐药性的治疗方法。
DOI：
10.1016/j.pharmthera.2020.107677
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发表时间：
2021-03
影响因子：
13.5
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang Y
HER2是一种众所周知的致癌受体酪氨酸激酶。约20%的乳腺癌（BC）发生HER2基因扩增，导致HER2蛋白过度表达，称为HER2阳性BC。HER2抑制剂可显著改善该亚型BC患者的预后。自1998年以来，已经开发了7种HER2抑制剂来治疗这种疾病。然而，耐药是常见的，仍然是一个主要的未解决的临床问题。病人通常在治疗一段时间后出现疾病进展。本文讨论了HER2信号传导的复杂性和多样性，所有HER2抑制剂的作用机制和治疗活性，HER2和其他信号蛋白在HER2阳性BC耐药中的作用，非细胞自主的耐药机制，以及肿瘤HER2表达的异质性。该综述提出了HER2阳性BC的耐药主要是由于HER2抑制剂无法消耗HER2的概念。还讨论了有望克服耐药性的新兴治疗方法。
HER2 is a well-known oncogenic receptor tyrosine kinase. HER2 gene amplification occurs in about 20% of breast cancer (BC), which leads to overexpression of HER2 protein, known as HER2-positive BC. Inhibitors of HER2 have significantly improved the prognosis of patients with this subset of BC. Since 1998, seven HER2 inhibitors have been developed to treat this disease. However, drug resistance is common and remains a major unresolved clinical problem. Patients typically show disease progression after some time on treatment. This review discusses the complexity and diversified nature of HER2 signaling, the mechanisms of actions and therapeutic activities of all HER2 inhibitors, the roles of HER2 and other signaling proteins in HER2-positive BC resistant to the inhibitors, the non-cell-autonomous mechanisms of drug resistance, and the heterogeneity of tumor HER2 expression. The review presents the concept that drug resistance in HER2-positive BC results primarily from the inability of HER2 inhibitors to deplete HER2. Emerging therapeutics that are promising for overcoming drug resistance are also discussed.
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