WWP1 ubiquitinates HER4 to mediate both proteasomal and lysosomal degradation[151]. the HER3-targeted therapies are licensed for utilization in clinical malignancy treatment because of their security and efficacy. Therefore, the development of Mouse monoclonal to XRCC5 HER3-targeted drugs possessing security, tolerability, and sensitivity is crucial for clinical malignancy 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 GRL0617 development of anticancer drugs targeting HER3. Keywords: HER3, molecular mechanism, drug resistance, targeted therapy, monoclonal antibody, molecular target INTRODUCTION Cancer ranks as the primary cause of mortality and a significant impediment to raising life expectancy worldwide[1]. Due to the frequent emergence of drug resistance after several cycles of chemotherapy, malignancy treatment often becomes inefficient[2]. Therefore, discovering new targets and developing new drugs are essential for malignancy therapy. Human epidermal growth factor receptor 3 (HER3/ErbB3) is usually a tyrosine kinase receptor belonging to the HER/ErbB receptor tyrosine kinase (RTK) family, along with the epidermal growth factor receptor EGFR/HER1, HER2/ErbB2/neu and HER4/ErbB4 in mammals[3,4]. Structurally, the HER3 protein comprises an extracellular domain name (ECD) that is responsible for binding ligands, which encompasses subdomains I-IV. HER3 also contains a transmembrane segment with hydrophobic properties and an intracellular domain name housing a juxtamembrane region, a segment with tyrosine kinase activity, and a carboxyterminal tail rich in tyrosine residues[5,6]. Neuregulins (NRGs) 1-2, also known as heregulins (HRGs), are the preferred ligands for HER3[7]. In the absence of a ligand, HER3 adopts an inactive conformation as a monomer. However, when a ligand attaches to subdomains I and III, HER3 undergoes a structural shift and exposes its arm for dimerization, allowing it to interact with another monomer and form a heterodimer[3,8]. HER3 prefers to dimerize with HER family members, including EGFR and HER2, but with a poor affinity to HER4[8]. Additionally, HER3 can dimerize with non-HER receptors, such as mesenchymal-epithelial transition (MET) factor receptor, fibroblast growth factor receptor 2 (FGFR2), and insulin-like growth factor receptor 1 (IGF-1R)[9-11]. HER3 is usually hard to create a homodimer and only possesses poor intracellular tyrosine kinase activity since it differs at crucial residues within the kinase domain name, resulting in its confinement in an inactive-like conformation[12,13]. Upon ligand binding, the kinase domain name of the dimerization partner phosphorylates the tyrosine residues in the C-terminal tail of HER3, subsequently initiating downstream signaling cascades[14]. HER3 plays a prominent role in the field of malignancy biology [Physique 1]. HER3 expression is usually linked to cell proliferation, invasion, metastasis, and poor overall survival in various malignancy types, including breast[15], prostate[16], lung[17], colorectal[18], melanoma[19], ovarian[20], gastric[21], pancreatic[22], head and neck cancer[23]. Moreover, HER3 can collaborate with other HER receptors to activate downstream signaling, such as activation of the PI3K/AKT, JAK/STAT, and MEK/MAPK pathways by HER2/HER3, or activation of the Src pathway by IGF-IR/HER3. The downstream effectors enter the nucleus to regulate the expression of relevant genes, which ultimately prospects to a wide range of processes, such as drug resistance[24]. Overall, HER3 can be a highly encouraging target for malignancy treatment. Open in a separate windows Physique 1 HER3 targeted therapies in the medical center and HER3 downstream signaling pathways. At present, the treatment strategies targeting HER3 in clinical trials mainly include monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates. Among them, monoclonal antibodies GRL0617 are the GRL0617 first developed agents with the most types. Since HER3 only has poor intracellular tyrosine kinase activity, HER3 is usually hard to be autophosphorylated but forms dimers with other receptors, including EGFR, HER2, and IGF-1R, especially HER2, and is phosphorylated by dimerization partner through transphosphorylation. HER2/HER3 dimers can activate PI3K/AKT, JAK/STAT, and MEK/MAPK pathways, but the Src kinase pathway is usually predominantly mediated by the IGF-1R/HER3 dimers. In addition, Src kinase and STAT protein can upregulate PI3K expression levels. Downstream effectors in the pathways such as mTOR, STAT, and MAPK can translocate into the nucleus and control the expression of multiple genes implicated in various processes involved in malignancy development, such as malignancy cell proliferation, survival, migration, invasion, apoptosis, differentiation, angiogenesis, cell cycle, and drug resistance. However, when antibodies bind to HER3 monomer or heterodimer, the signaling pathway downstream of HER3 is usually blocked, subsequently inhibiting the malignancy progression..