Human epidermal growth factor receptor 3 (HER3)-containing heterodimer (HER3 heterodimer)

Human epidermal growth factor receptor 3 (HER3), or ErbB3, is a member of the receptor tyrosine kinase family characterized by a catalytically inactive kinase domain, necessitating its dimerization with other HER family members to initiate signaling (UniProt P35041). The formation of HER3-containing heterodimers, most notably with HER2 or EGFR, creates a potent signaling platform that primarily activates the phosphoinositide 3-kinase (PI3K)/AKT pathway, driving cell proliferation and survival (PubMed: 11252954). These heterodimers play a pivotal role in various malignancies, including breast, lung, and gastric cancers, and are frequently associated with acquired resistance to existing EGFR and HER2 inhibitors (PubMed: 22496104). Because HER3 lacks strong intrinsic kinase activity, drug development has focused on blocking its ability to dimerize or bind its ligand, neuregulin, using monoclonal and bispecific antibodies (PubMed: 25501946). Additionally, HER3-containing heterodimers are targeted by novel antibody-drug conjugates (ADCs) that utilize the receptor for the specific delivery of cytotoxic agents to tumor cells (Daiichi Sankyo, 2023). The clinical significance of these dimers is further highlighted by the discovery of NRG1 gene fusions, which lead to constitutive HER3 activation and represent a distinct therapeutic vulnerability (Nature Reviews Clinical Oncology, 2021). Overall, targeting HER3-containing heterodimers represents a sophisticated approach to overcoming bypass signaling and improving outcomes in HER-family driven cancers.

Other names

ErbB3 heterodimerHER3/HER2 complexHER3/EGFR complexHER3/ErbB2 complexHER3/ErbB1 complexNeuregulin receptor complex

Inhibition of ligand-induced dimerization, blockade of neuregulin binding, and induction of receptor internalization or antibody-dependent cellular cytotoxicity (ADCC).