HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs

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.