Bailey Tameka A, Luan Haitao, Clubb Robert J, Naramura Mayumi, Band Vimla, Raja Srikumar M, Band Hamid
Eppley Institute for Research in Cancer and Allied Diseases, College of Medicine, University of Nebraska Medical Center, 985950 Nebraska Medical Center Omaha, NE, USA.
J Carcinog. 2011;10:28. doi: 10.4103/1477-3163.90442. Epub 2011 Nov 30.
The Human Epidermal Growth Factor Receptor 2 (Her2, ErbB2 or Neu) is overexpressed in about 20 - 25% of breast cancers and is causally linked to oncogenesis, providing opportunities for targeted therapy. Trastuzumab (Herceptin(™), Genentech Inc, San Francisco, CA), a humanized monoclonal antibody against ErbB2, is a successful example of this concept and has vastly improved the response to treatment and overall survival in a majority of ErbB2+ breast cancer patients. However, lack of response in some patients as well as relapse during the course of therapy in others, continue to challenge researchers and clinicians alike towards a better understanding of the fundamental mechanisms of Trastuzumab action and resistance to treatment. The exact in vivo mechanism of action of Trastuzumab remains enigmatic, given its direct effects on the ErbB2 signaling pathway as well as indirect contributions from the immune system, by virtue of the ability of Trastuzumab to elicit Antibody-Dependent Cellular Cytotoxicity. Consequently, multiple mechanisms of resistance have been proposed. We present here a comprehensive review of our current understanding of the mechanisms, both of Trastuzumab action and clinical resistance to Trastuzumab-based therapies. We also review newer strategies (based on ErbB2 receptor biology) that are being explored to overcome resistance to Trastuzumab therapy.
人表皮生长因子受体2（Her2、ErbB2或Neu）在约20%-25%的乳腺癌中过度表达，并且与肿瘤发生存在因果联系，这为靶向治疗提供了机会。曲妥珠单抗（赫赛汀（™），基因泰克公司，加利福尼亚州旧金山），一种针对ErbB2的人源化单克隆抗体，就是这一概念的成功范例，并且极大地改善了大多数ErbB2阳性乳腺癌患者的治疗反应和总生存期。然而，一些患者缺乏反应以及其他患者在治疗过程中复发，这继续向研究人员和临床医生提出挑战，促使他们更好地理解曲妥珠单抗作用和治疗耐药性的基本机制。鉴于曲妥珠单抗对ErbB2信号通路的直接作用以及免疫系统的间接作用，凭借曲妥珠单抗引发抗体依赖性细胞毒性的能力，曲妥珠单抗在体内的确切作用机制仍然不明。因此，已经提出了多种耐药机制。我们在此全面综述目前对曲妥珠单抗作用机制以及基于曲妥珠单抗治疗的临床耐药性机制的理解。我们还综述了正在探索的（基于ErbB2受体生物学的）新策略，以克服对曲妥珠单抗治疗的耐药性。
