Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan; Department of Oncology and Hemato-Oncology, University of Milan, Milan. Electronic address: https://twitter.com/jacopo_uli.
Division of New Drugs and Early Drug Development, European Institute of Oncology IRCCS, Milan; Department of Oncology and Hemato-Oncology, University of Milan, Milan; Department of Medicine, University of Udine, Udine, Italy. Electronic address: https://twitter.com/carlacorvaja.
ESMO Open. 2023 Feb;8(1):100790. doi: 10.1016/j.esmoop.2023.100790. Epub 2023 Feb 8.
Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 and/or epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment.
人类表皮生长因子受体 3（HER3）是人类表皮生长因子受体家族的一员，其主要配体是神经调节蛋白 1 和 2。尽管其酪氨酸激酶活性较弱，但 HER3 可以与 HER2 和/或表皮生长因子受体（EGFR）异二聚化，导致下游信号转导途径的磷酸化和激活急剧增强，最终促进肿瘤发生、转移扩散和耐药性。鉴于其在实体瘤中的广泛表达，已经进行了多种努力通过阻断配体结合域或与其他受体的二聚化来治疗性靶向 HER3。抗 HER3 单克隆抗体或双特异性抗体的治疗，无论是作为单一药物还是与其他化合物联合使用，在几种肿瘤类型中均导致令人不满意的结果。通过抗体药物偶联物将细胞毒性有效载荷靶向 HER3 最近在几种肿瘤类型中显示出令人鼓舞的活性，这表明 HER3 的治疗性靶向在癌症治疗中具有潜在作用。
