Human epidermal growth factor receptor 3–Epidermal growth factor receptor (HER3–EGFR) dimer interface (HER3–EGFR dimer interface)

The Human epidermal growth factor receptor 3–Epidermal growth factor receptor (HER3–EGFR) dimer interface is a critical protein-protein interaction site that facilitates potent oncogenic signaling. While HER3 is often classified as a pseudokinase due to its impaired catalytic activity, it serves as a powerful allosteric activator of its dimerization partners, including EGFR and HER2 (Littlefield et al., 2014, Sci Signal). Upon ligand binding, such as Neuregulin-1 or EGF, these receptors form heterodimers where the C-lobe of one kinase domain activates the N-lobe of the other, leading to the phosphorylation of the HER3 C-terminal tail (Schaefer et al., 2011, Cancer Cell). This process creates high-affinity docking sites for the p85 subunit of PI3K, making the HER3–EGFR dimer a primary driver of the PI3K/Akt/mTOR survival pathway (UniProt P21860). In many cancers, particularly those resistant to first-generation EGFR inhibitors, the formation of this dimer serves as a bypass mechanism to maintain signaling (Jacobsen et al., 2017, Oncotarget). Therapeutic strategies targeting this interface include bispecific antibodies like duligotuzumab, which simultaneously block ligand binding to both receptors and sterically hinder their association (Schaefer et al., 2011, Cancer Cell). Targeting the interface is particularly relevant in overcoming resistance in non-small cell lung cancer and colorectal cancer where HER3 upregulation is a frequent occurrence.

Other names

ErbB3–ErbB1 heterodimer interfaceHER3–EGFR heterodimerEGFR–HER3 signaling complexHER3–EGFR interface

The mechanism of action involves the use of therapeutic antibodies to bind the extracellular domains of EGFR and HER3, thereby sterically blocking their ability to form a functional heterodimer. This prevents the allosteric activation of the EGFR kinase domain by HER3 and inhibits the recruitment of PI3K to the HER3 C-terminal tail, effectively shutting down the PI3K/Akt and MAPK signaling pathways (Schaefer et al., 2011, Cancer Cell; Littlefield et al., 2014, Sci Signal).