ErbB receptor tyrosine kinase 3 (ERBB3) (ERBB3)

ErbB receptor tyrosine kinase 3 (ERBB3), also known as HER3, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (UniProt P21860). Unlike other members of the family, ERBB3 possesses minimal intrinsic kinase activity and functions primarily through heterodimerization with other family members, most notably HER2 and EGFR (Sithanandam & Kollohe, 2008). Upon ligand binding, typically Neuregulin-1, ERBB3 undergoes a conformational change that allows it to dimerize, leading to the transphosphorylation of its cytoplasmic tail by its partner kinase (Haikala et al., 2022). This phosphorylation creates high-affinity docking sites for the p85 subunit of phosphoinositide 3-kinase (PI3K), making ERBB3 a potent activator of the PI3K/Akt/mTOR survival pathway (PubMed: 11087443). In oncology, ERBB3 is frequently overexpressed or mutated and is a major driver of resistance to therapies targeting EGFR and HER2 (Mishra et al., 2018). Therapeutic strategies include monoclonal antibodies that block dimerization and antibody-drug conjugates, such as Patritumab deruxtecan, designed to exploit ERBB3 expression for targeted delivery of cytotoxic agents (Jhaveri et al., 2023).

Other names

HER3Human epidermal growth factor receptor 3LCCS2ErbB-3c-erbB3p185-erbB3

Drugs targeting this system primarily act by binding to the extracellular domain of ERBB3 to inhibit ligand binding (e.g., Neuregulin-1) and prevent the conformational change required for heterodimerization with EGFR or HER2, thereby blocking the transphosphorylation of the ERBB3 cytoplasmic tail (Sithanandam & Kollohe, 2008). Antibody-drug conjugates (ADCs) utilize ERBB3 as a target for internalization to deliver cytotoxic payloads directly into tumor cells (Jhaveri et al., 2023). Bispecific antibodies may also be used to simultaneously target ERBB3 and its dimerization partners to prevent signaling (Geuijen et al., 2018).