Desai Omkar, Rathore Moeez, Boutros Christina S, Wright Michel'le, Bryson Elizabeth, Curry Kimberly, Wang Rui
Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA.
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Genes Dis. 2024 Jun 17;12(4):101354. doi: 10.1016/j.gendis.2024.101354. eCollection 2025 Jul.
HER3, formally referred to as ERB-B2 receptor tyrosine kinase 3, is a member of the ErbB receptor tyrosine kinases (also known as EGFR) family. HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation, which initiates downstream signaling pathways crucial in cancer cell survival and progression. As a result, numerous monoclonal antibodies have been developed to block HER3 activation and subsequent signaling pathways. While pre-clinical investigations have effectively showcased significant anti-cancer effects of HER3-targeted therapies, these therapies have had little impact on cancer patient outcomes in the clinic, except for patients with rare fusion mutations. This review offers a comprehensive description of the oncogenic functions of HER3, encompassing its structure and mediating signaling pathways. More importantly, it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical determinants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies. Lastly, we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.
HER3，正式名称为ERB-B2受体酪氨酸激酶3，是表皮生长因子受体（EGFR）家族的成员之一，属于ErbB受体酪氨酸激酶家族。由于HER3的过表达和异常激活，它在多种类型的癌症中发挥着重要的促癌作用，这种激活会启动对癌细胞存活和进展至关重要的下游信号通路。因此，人们已经开发了许多单克隆抗体来阻断HER3的激活及后续信号通路。虽然临床前研究有效地展示了HER3靶向治疗的显著抗癌效果，但除了患有罕见融合突变的患者外，这些疗法在临床上对癌症患者的预后影响甚微。本综述全面描述了HER3的致癌功能，包括其结构和介导的信号通路。更重要的是，它深入探讨了过去和正在进行的针对不同类型癌症的HER3靶向治疗的临床试验，并讨论了肿瘤微环境和其他关键决定因素，这些因素可能导致在大多数使用HER3靶向治疗的临床研究中观察到的不理想结果。最后，我们建议采用替代方法并探索新策略，以在未来的转化研究中潜在地提高靶向关键致癌HER3信号通路的疗效。
