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.

HER2是众所周知的致癌受体酪氨酸激酶。HER2大约 20% 的乳腺癌 (BC) 发生基因扩增，导致 HER2 蛋白过表达，称为 HER2 阳性 BC。HER2 抑制剂显着改善了该亚型 BC 患者的预后。自 1998 年以来，已开发出七种 HER2 抑制剂来治疗这种疾病。然而，耐药性很常见，并且仍然是一个主要的未解决的临床问题。患者通常在治疗一段时间后表现出疾病进展。本综述讨论了 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 中对抑制剂耐药的作用、非细胞自主机制耐药性和肿瘤 HER2 表达的异质性。该综述提出了这样一个概念，即 HER2 阳性 BC 中的耐药性主要是由于 HER2 抑制剂无法耗尽 HER2。还讨论了有望克服耐药性的新兴疗法。