Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer.
Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer.
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DOI：
10.18632/oncotarget.7043
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发表时间：
2016-09-27
期刊：
影响因子：
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通讯作者：
Hortobagyi GN
中科院分区：
文献类型：
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作者：
de Melo Gagliato D;Jardim DL;Marchesi MS;Hortobagyi GN
乳腺癌(BC)是一种高度流行的疾病。一名生活在美国的女性一生中被诊断出患有乳腺癌的风险为12.3%。它是最常见的女性癌症，也是女性癌症死亡的第二大常见原因。值得注意的是，人表皮受体2(HER2)癌基因扩增或过表达存在于大约18%至20%的原发浸润性乳腺癌中，在针对这一特定BC亚型的个性化治疗之前，与包括三重阴性BC(TNBC)在内的所有其他类型相比，HER2+BC组的总体生存率(OS)和无复发生存率(RFS)是最差的。HER2是表皮生长因子受体(EGFR)家族成员。其他家族成员包括EGFR或HER1、HER3和HER4。HER2可以与其他三种受体中的任何一种形成异二聚体，被认为是其他HER或ErbB受体的首选二聚体。胞浆内酪氨酸残基的磷酸化是受体二聚化的结果，最终导致多种信号通路的启动，参与细胞的增殖、转录、运动和细胞凋亡抑制。HER2的过度表达除了是诊断为BC的妇女的一个重要预后因素外，还确定了那些从针对HER2的药物治疗中受益的患者，如曲妥珠单抗、pertuzumab、曲妥珠单抗、曲妥珠单抗和HER2的小分子酪氨酸激酶抑制剂[，127]。事实上，曲妥珠单抗在很大程度上改变了被诊断为HER2+BC患者的自然病史，无论是在早期疾病还是在转移疾病的背景下。然而，尽管在疾病早期接受了抗HER2治疗，但仍有许多女性最终会发展为转移性疾病。此外，晚期肿瘤可能达到任何抗HER2治疗都无法实现疾病控制的地步，包括最近批准的药物，如T-DM1。这篇综述文章将集中于最终导致BC对抗HER2治疗产生耐药性的主要生物学途径，并总结其机制。克服这种阻力的策略，以及每种逆转这种情况的策略所涉及的基本原理都将呈现给读者。
Breast Cancer (BC) is a highly prevalent disease. A woman living in the United States has a 12.3% lifetime risk of being diagnosed with breast cancer. It is the most common female cancer and the second most common cause of cancer death in women. Of note, amplification or overexpression of Human Epidermal Receptor 2 (HER2) oncogene is present in approximately 18 to 20% of primary invasive breast cancers, and until personalized therapy became available for this specific BC subtype, the worst rates of Overall Survival (OS) and Recurrence-Free Survival (RFS) were observed in the HER2+ BC cohort, compared to all other types, including triple negative BC (TNBC). HER2 is a member of the epidermal growth factor receptor (EGFR) family. Other family members include EGFR or HER1, HER3 and HER4. HER2 can form heterodimers with any of the other three receptors, and is considered to be the preferred dimerization partner of the other HER or ErbB receptors. Phosphorylation of tyrosine residues within the cytoplasmic domain is the result of receptor dimerization and culminates into initiation of a variety of signalling pathways involved in cellular proliferation, transcription, motility and apoptosis inhibition. In addition to being an important prognostic factor in women diagnosed with BC, HER2 overexpression also identifies those patients who benefit from treatment with agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [, 127]. In fact, trastuzumab altered the natural history of patients diagnosed with HER2+ BC, both in early and metastatic disease setting, in a major way. Nevertheless, there are many women that will eventually develop metastatic disease, despite being treated with anti-HER2 therapy in the early disease setting. Moreover, advanced tumors may reach a point where no anti-HER2 treatment will achieve disease control, including recently approved drugs, such as T-DM1. This review paper will concentrate on major biological pathways that ultimately lead to resistance to anti-HER2 therapies in BC, summarizing their mechanisms. Strategies to overcome this resistance, and the rationale involved in each tactics to revert this scenario will be presented to the reader.