Zeng Huilan, Wang Wei, Zhang Lin, Lin Zhenghong
School of Life Sciences, Chongqing University, Chongqing 401331, China.
Department of Cancer Center, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Chongqing 404000, China.
Cancer Drug Resist. 2024 Apr 29;7:14. doi: 10.20517/cdr.2024.11. eCollection 2024.
Human epidermal growth factor receptor 3 (HER3), which is part of the HER family, is aberrantly expressed in various human cancers. Since HER3 only has weak tyrosine kinase activity, when HER3 ligand neuregulin 1 (NRG1) or neuregulin 2 (NRG2) appears, activated HER3 contributes to cancer development and drug resistance by forming heterodimers with other receptors, mainly including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Inhibition of HER3 and its downstream signaling, including PI3K/AKT, MEK/MAPK, JAK/STAT, and Src kinase, is believed to be necessary to conquer drug resistance and improve treatment efficiency. Until now, despite multiple anti-HER3 antibodies undergoing preclinical and clinical studies, none of the HER3-targeted therapies are licensed for utilization in clinical cancer treatment because of their safety and efficacy. Therefore, the development of HER3-targeted drugs possessing safety, tolerability, and sensitivity is crucial for clinical cancer treatment. This review summarizes the progress of the mechanism of HER3 in drug resistance, the HER3-targeted therapies that are conducted in preclinical and clinical trials, and some emerging molecules that could be used as future designed drugs for HER3, aiming to provide insights for future research and development of anticancer drugs targeting HER3.
人表皮生长因子受体3（HER3）是HER家族的一部分，在多种人类癌症中异常表达。由于HER3仅具有较弱的酪氨酸激酶活性，当HER3配体神经调节蛋白1（NRG1）或神经调节蛋白2（NRG2）出现时，激活的HER3通过与其他受体形成异二聚体，主要包括表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2），从而促进癌症发展和耐药性。抑制HER3及其下游信号通路，包括PI3K/AKT、MEK/MAPK、JAK/STAT和Src激酶，被认为是克服耐药性和提高治疗效果所必需的。到目前为止，尽管多种抗HER3抗体正在进行临床前和临床研究，但由于其安全性和有效性，尚无一种HER3靶向疗法被批准用于临床癌症治疗。因此，开发具有安全性、耐受性和敏感性的HER3靶向药物对于临床癌症治疗至关重要。本综述总结了HER3在耐药性机制方面的进展、正在进行临床前和临床试验的HER3靶向疗法，以及一些可作为未来HER3设计药物的新兴分子，旨在为未来靶向HER3的抗癌药物研发提供见解。
