Human epidermal growth factor receptor 2 (HER2) and Human epidermal growth factor receptor 3 (HER3) (HER2, HER3)

Human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3) are closely related members of the epidermal growth factor receptor (EGFR/HER/ERBB) family of receptor tyrosine kinases, which also includes EGFR (HER1/ERBB1) and HER4 (ERBB4)[4][5][6]. Both are single-pass transmembrane proteins with extracellular ligand-binding domains and intracellular kinase domains. HER2 does not have a known endogenous ligand and exists in an active-looking conformation, predisposed to dimerization[4][1]. HER3, though structurally similar, has highly impaired kinase activity and relies on dimerization with other HER family members, particularly HER2, to transduce growth signals[4][1]. The HER2-HER3 heterodimer is the most potent signaling unit of the HER family, efficiently activating PI3K/AKT and MAPK pathways, and driving oncogenic processes such as cell proliferation, survival, and tumor progression[4][3][6]. Overexpression or mutational activation of HER2 is a major oncogenic driver, particularly in breast cancer, and can render tumors highly dependent on HER2/HER3 signaling. As a result, both receptors are therapeutic targets; anti-HER2 therapies including monoclonal antibodies and small molecule inhibitors are standards of care in HER2-amplified breast cancers, while anti-HER3 strategies are being developed to combat resistance and improve outcomes[4][5][1].

Other names

ERBB2Neu (rat homolog)Receptor tyrosine-protein kinase erbB-2ERBB3Receptor tyrosine-protein kinase erbB-3

Inhibition of receptor dimerization (e.g., pertuzumab) - Blockade of extracellular domain (e.g., trastuzumab) - Inhibition of intracellular tyrosine kinase activity (e.g., lapatinib, neratinib) - Antibody–drug conjugate delivery to HER2-expressing tumors (e.g., trastuzumab deruxtecan) - Disruption of downstream PI3K/AKT and MAPK signaling pathways