Human epidermal growth factor receptor 3 heterodimer (HER3 heterodimer)

Human epidermal growth factor receptor 3 (HER3) heterodimers are functional signaling complexes formed between HER3 (ErbB3) and other members of the ErbB family, most notably HER2 (ErbB2) or EGFR (ErbB1). Because HER3 possesses a pseudokinase domain with minimal intrinsic catalytic activity, it is largely inactive as a homodimer and must undergo heterodimerization to initiate intracellular signaling (UniProt: P35041). The HER2/HER3 heterodimer is recognized as one of the most potent oncogenic signaling units, primarily driving the PI3K/Akt/mTOR pathway which promotes tumor cell survival, growth, and metabolic reprogramming (PMID: 24510944). In many clinical contexts, the activation of HER3-containing heterodimers serves as a major escape mechanism, conferring resistance to therapies targeting EGFR or HER2, such as tyrosine kinase inhibitors or monoclonal antibodies (PMID: 30217984). Therapeutic strategies targeting these complexes include bispecific antibodies that bridge HER2 and HER3, and monoclonal antibodies that block the binding of the ligand neuregulin. Recently, antibody-drug conjugates (ADCs) like patritumab deruxtecan have shown significant promise by utilizing HER3 expression to deliver potent topoisomerase I inhibitors directly into malignant cells (NCT04619004).

Other names

ErbB3 heterodimerHER3/HER2 complexHER3/EGFR complexHER3/ErbB2 complexHER3/ErbB heterodimerKinase-impaired ErbB3 complex

Inhibition of ligand-induced dimerization, blockade of neuregulin (NRG1) binding to the HER3 extracellular domain, and targeted delivery of cytotoxic payloads via antibody-drug conjugates (ADCs) to inhibit downstream PI3K/Akt signaling (PMID: 32814730).