Receptor tyrosine-protein kinase erbB-3 (HER3) (HER3)

Receptor tyrosine-protein kinase erbB-3 (HER3) is a member of the human epidermal growth factor receptor (ErbB) family, characterized by its unique status as a pseudokinase due to an impaired intracellular kinase domain [1, 2]. Despite its lack of intrinsic catalytic activity, HER3 plays a pivotal role in oncogenic signaling by acting as a preferred heterodimerization partner for other ErbB receptors, particularly HER2 and EGFR [2, 3]. Upon binding its ligand, neuregulin (NRG), the extracellular domain (ECD) of HER3 undergoes a conformational shift that enables these interactions, subsequently triggering the potent PI3K/Akt/mTOR signaling pathway which promotes cell survival and proliferation [3, 5]. In many cancers, including breast and lung, HER3 overexpression is associated with poor prognosis and serves as a key mechanism of resistance to existing EGFR and HER2 inhibitors [2, 5]. Therapeutic strategies focusing on the HER3 extracellular domain include monoclonal antibodies that block ligand binding or dimerization, and antibody-drug conjugates (ADCs) like patritumab deruxtecan that leverage the receptor for targeted delivery of cytotoxic payloads [4]. These interventions aim to bypass the signaling redundancies that often lead to treatment failure in advanced malignancies [3, 4].

Other names

ErbB3Human epidermal growth factor receptor 3LCCS2MDA-BF-1p185-erbB3p45-sErbB3p85-sErbB3

Therapeutic agents target the extracellular domain (ECD) of HER3 to inhibit ligand (neuregulin) binding, prevent heterodimerization with other ErbB family members, and induce receptor internalization or antibody-dependent cellular cytotoxicity (ADCC) [2, 3, 5]. Antibody-drug conjugates (ADCs) specifically utilize the HER3 ECD as a cell-surface anchor to internalize and release cytotoxic payloads within the tumor cell [4].