Campbell Marcia R, Zhang Hui, Ziaee Shabnam, Ruiz-Saenz Ana, Gulizia Nathaniel, Oeffinger Julie, Amin Dhara N, Ahuja Deepika, Moasser Mark M, Park Catherine C
Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1708, San Francisco, CA, 94143, USA.
Breast Cancer Res Treat. 2016 Feb;155(3):431-40. doi: 10.1007/s10549-016-3698-y. Epub 2016 Feb 9.
The central role of HER2 as the disease driver and HER3 as its essential partner has made them rational targets for the treatment of HER2-amplifed breast cancers, and there is considerable interest in developing highly effective treatment regimens for this disease that consist of targeted therapies alone. Much of these efforts are focused on dual targeting approaches, particularly dual targeting of the HER2-HER3 tumor driver complex itself, or vertical combinations that target downstream PI3K or Akt in addition to HER2. There is also potential in lateral combinations based on evidence implicating cross-talk with other membrane receptor systems, particularly integrins, and such lateral combinations can potentially involve either HER2 or HER3. We established a preclinical model of targeting HER3 using doxycycline-inducible shRNA and determined the efficacy of a β1 integrin inhibitor in combination with targeting HER3. We report that targeting HER3 and β1 integrin provides a particularly effective combination therapy approach for HER2-amplified cancers, surpassing the combination of HER2 and β1 integrin targeting, and evading some of the safety concerns associated with direct HER2-targeting. This further validates HER3 as a major hub mediating the tumorigenic functions of HER2 and identifies it as a high value target for lateral combination therapy strategies.
HER2作为疾病驱动因子的核心作用以及HER3作为其关键伙伴的作用，使其成为HER2扩增型乳腺癌治疗的合理靶点，并且人们对仅由靶向疗法组成的针对该疾病的高效治疗方案有着浓厚兴趣。这些努力大多集中在双重靶向方法上，特别是对HER2-HER3肿瘤驱动复合物本身的双重靶向，或者是除HER2之外还靶向下游PI3K或Akt的纵向联合。基于涉及与其他膜受体系统（特别是整合素）相互作用的证据，横向联合也具有潜力，这种横向联合可能涉及HER2或HER3。我们利用强力霉素诱导的shRNA建立了靶向HER3的临床前模型，并确定了β1整合素抑制剂与靶向HER3联合使用的疗效。我们报告称，靶向HER3和β1整合素为HER2扩增型癌症提供了一种特别有效的联合治疗方法，超过了HER2和β1整合素靶向联合，并且规避了一些与直接靶向HER2相关的安全问题。这进一步验证了HER3作为介导HER2致癌功能的主要枢纽，并将其确定为横向联合治疗策略的高价值靶点。
