Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Ann Oncol. 2010 Oct;21 Suppl 7:vii36-40. doi: 10.1093/annonc/mdq421.
The HER family of receptors consists of four closely related type 1 transmembrane TK receptors: HER1 (EGFR), HER2, HER3 and HER4. Signalling via the HER family of receptors underpins the majority of the intricate array of cellular activities on which cell survival and functionality depend. Aberrant HER2 expression and/or functionality have been implicated in the evolution of breast cancer and this receptor has proved to be a potent target for anticancer therapies, including antibody-based therapies to prevent ligand binding, dimer formation or the recruitment of antibody-dependent cell-mediated cytotoxicity, and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners. Novel strategies against HER2 include HER tyrosine kinase inhibitors, HSP90 inhibitors and antibody-chemotherapy conjugates. This latter approach is exemplified by T-DM1, a potent antibody that has a good safety profile and that has shown remarkable activity in patients with advanced disease. In addition, pertuzumab, an mAb that directly inhibits the formation of HER2 dimers including the HER2:HER3 dimer, offers a unique mechanism of HER3 inhibition. All these approaches have shown substantial clinical activity in patients refractory to trastuzumab. It is anticipated that with the increased availability of novel anti-HER2 agents together with a better understanding of the mechanisms of resistance to anti-HER2 agents we should be able to further improve the outcome of patients with HER2 breast cancer. There will also be an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting.
HER 家族受体由四个密切相关的 1 型跨膜 TK 受体组成：HER1（EGFR）、HER2、HER3 和 HER4。通过 HER 家族受体的信号转导支撑着细胞生存和功能所依赖的绝大多数复杂的细胞活动。HER2 的异常表达和/或功能已被牵连到乳腺癌的演变中，并且该受体已被证明是癌症治疗的有效靶点，包括针对配体结合、二聚体形成或抗体依赖的细胞介导的细胞毒性募集的抗体治疗，以及直接的激酶抑制以防止分子激活和下游信号伙伴的募集。针对 HER2 的新策略包括 HER 酪氨酸激酶抑制剂、HSP90 抑制剂和抗体-化疗偶联物。后一种方法的代表是 T-DM1，这是一种有效的抗体，具有良好的安全性，并在晚期疾病患者中显示出显著的活性。此外，帕妥珠单抗是一种直接抑制 HER2 二聚体形成的 mAb，包括 HER2:HER3 二聚体，提供了一种独特的 HER3 抑制机制。所有这些方法在对曲妥珠单抗耐药的患者中都显示出显著的临床活性。随着新型抗 HER2 药物的增加以及对这些药物的耐药机制的更好理解，预计我们应该能够进一步改善 HER2 阳性乳腺癌患者的预后。这些药物的研究也将越来越倾向于疾病的早期阶段，即辅助和新辅助治疗。
