Receptor tyrosine-protein kinase erbB-3 (ErbB3) (ErbB3)

Receptor tyrosine-protein kinase erbB-3, commonly known as HER3, is a member of the human epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases (UniProt P21860). Unlike other members of this family, ErbB3 possesses a catalytically impaired kinase domain, classifying it as a pseudokinase that requires heterodimerization with other family members, most notably HER2 or EGFR, to initiate intracellular signaling (Haikala & Jänne, 2021). Upon ligand binding (primarily neuregulins) to its extracellular domain, ErbB3 undergoes a conformational change that allows it to dimerize and potently activate the PI3K/Akt/mTOR pathway, which is essential for cell growth, survival, and metabolic regulation (Sithanandam & Mozeika, 2010). In oncology, ErbB3 is frequently overexpressed or co-activated, serving as a key mediator of resistance to therapies targeting EGFR and HER2 (Jänne et al., 2022). Current therapeutic strategies focus on the extracellular domain using monoclonal antibodies to block signaling or antibody-drug conjugates (ADCs) like patritumab deruxtecan that utilize the receptor for targeted delivery of cytotoxic agents (ClinicalTrials.gov).

Other names

HER3Human epidermal growth factor receptor 3ErbB-3LCCS2Proto-oncogene-like protein c-ErbB-3MDA-BF-1

Drugs targeting the ErbB3 extracellular domain primarily work by blocking the binding of neuregulin ligands or preventing the receptor from adopting an active conformation necessary for heterodimerization with HER2 or EGFR (Haikala & Jänne, 2021). This inhibition prevents the phosphorylation of the ErbB3 C-terminal tail and the subsequent recruitment of PI3K, thereby suppressing the Akt survival pathway (Sithanandam & Mozeika, 2010). Additionally, antibody-drug conjugates (ADCs) bind to the extracellular domain to trigger receptor-mediated endocytosis, allowing for the intracellular release of potent cytotoxins (Jänne et al., 2022).