Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, Monash University, Melbourne, Australia; Department of Medical Oncology, Austin Hospital, Melbourne, Australia.
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; Department of Medical Oncology, Austin Hospital, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia.
Crit Rev Oncog. 2020;25(3):175-207. doi: 10.1615/CritRevOncog.2020036080.
Human epidermal growth factor receptor 2 (HER2) oncogene addiction has led to the development of anti-HER2 therapies which have revolutionized the management of patients with HER2-positive cancers, with trastuzumab being the cornerstone of treatment of HER2-positive breast cancer. Despite the success of these biologics in breast cancer patients, not all patients with HER2-positive tumors respond to treatment, and many eventually develop resistance to therapy. Developing therapies that that circumvent current resistance mechanisms and improve patient outcomes further remains an area of unmet clinical need. Based on insights gained from established anti-HER2 therapies and our understanding of known resistance mechanisms a number of novel anti-HER2 treatments are being developed. These include novel HER2 antibody-drug conjugates that have shown activity in HER2 high and low tumors, novel HER2 antibodies, T cell bispecific antibodies, and HER2 antibodies in combination with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, immunotherapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. In this article, we review resistance mechanisms to approved HER2 antibodies and provide an overview of emerging therapeutic agents.
人表皮生长因子受体 2 (HER2) 癌基因成瘾导致了抗 HER2 治疗的发展，彻底改变了 HER2 阳性癌症患者的治疗管理，曲妥珠单抗是治疗 HER2 阳性乳腺癌的基石。尽管这些生物制剂在乳腺癌患者中取得了成功，但并非所有 HER2 阳性肿瘤患者对治疗都有反应，许多患者最终对治疗产生耐药性。开发能够规避当前耐药机制并进一步改善患者预后的治疗方法仍然是一个未满足的临床需求领域。基于从已确立的抗 HER2 治疗中获得的见解和我们对已知耐药机制的理解，正在开发许多新型抗 HER2 治疗方法。这些方法包括在 HER2 高和低肿瘤中显示出活性的新型 HER2 抗体-药物偶联物、新型 HER2 抗体、T 细胞双特异性抗体以及与磷脂酰肌醇 3-激酶 (PI3K)/雷帕霉素靶蛋白 (mTOR) 抑制剂、免疫疗法和细胞周期蛋白依赖性激酶 4/6 (CDK4/6) 抑制剂联合使用的 HER2 抗体。本文综述了已批准的 HER2 抗体的耐药机制，并概述了新兴的治疗药物。
