Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin.
Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin.
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DOI：
10.1007/s10549-016-3698-y
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发表时间：
2016-02
影响因子：
3.8
通讯作者：
Park CC
中科院分区：
文献类型：
--
作者：
Campbell MR;Zhang H;Ziaee S;Ruiz-Saenz A;Gulizia N;Oeffinger J;Amin DN;Ahuja D;Moasser MM;Park CC
HER 2作为疾病驱动因素和HER 3作为其重要伙伴的核心作用使其成为治疗HER 2扩增乳腺癌的合理靶点，并且对开发由单独靶向治疗组成的针对该疾病的高效治疗方案有相当大的兴趣。这些努力中的大部分集中在双重靶向方法上，特别是HER 2-HER 3肿瘤驱动复合物本身的双重靶向，或除了HER 2之外还靶向下游PI 3 K或Akt的垂直组合。基于涉及与其他膜受体系统（特别是整合素）的串扰的证据，也存在横向组合的可能性，并且此类横向组合可能涉及HER 2或HER 3。我们建立了一个使用强力霉素诱导的shRNA靶向HER 3的临床前模型，并确定了β1整联蛋白抑制剂与靶向HER 3组合的疗效。我们报告，靶向HER 3和β1整联蛋白为HER 2扩增的癌症提供了一种特别有效的联合治疗方法，超过了HER 2和β1整联蛋白靶向的联合治疗，并避免了与直接HER 2靶向相关的一些安全性问题。这进一步验证了HER 3作为介导HER 2的致瘤功能的主要枢纽，并将其鉴定为侧向联合治疗策略的高价值靶标。
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.