Human epidermal growth factor receptor 2 extracellular domain II (HER2 ECD II)

HER2 extracellular domain II (ECD II) is a critical structural component of the Human Epidermal Growth Factor Receptor 2 (HER2), a member of the ErbB family of receptor tyrosine kinases [5, 9]. Unlike other family members, HER2 lacks a known ligand and remains in an open, active conformation that facilitates dimerization with other receptors like HER3 [11, 14]. Domain II specifically serves as the dimerization arm, enabling the formation of heterodimers that initiate intracellular signaling cascades responsible for cell proliferation and survival [9, 16]. In various malignancies, most notably HER2-positive breast and gastric cancers, the overexpression of HER2 leads to excessive signaling and aggressive tumor growth [13, 15]. This domain is the primary target for the monoclonal antibody pertuzumab and its biosimilars, such as Pectuna [2, 3]. By binding to ECD II, these drugs sterically block the dimerization process, effectively shutting down downstream oncogenic pathways like PI3K/AKT [11, 12]. Additionally, the binding of these antibodies can trigger antibody-dependent cellular cytotoxicity (ADCC), recruiting the immune system to target and eliminate cancer cells [15]. Therapeutic targeting of this domain has significantly improved clinical outcomes for patients with HER2-amplified tumors [6, 11].

Other names

ERBB2 domain IIHER2 subdomain IIHER2 dimerization domainCD340 domain IINEU domain II

Inhibition of HER2 dimerization (specifically heterodimerization with HER3) to block downstream signaling pathways (PI3K/AKT and MAPK) and induction of antibody-dependent cellular cytotoxicity (ADCC) [11, 15, 16].