Epidermal growth factor receptor-Erb-B2 receptor tyrosine kinase 2 heterodimer (EGFR-HER2 heterodimer)

The Epidermal growth factor receptor (EGFR) and Erb-B2 receptor tyrosine kinase 2 (HER2) heterodimer is a high-affinity signaling complex formed by two members of the ErbB family (UniProt: P00533, P04626). Unlike other members, HER2 has no known high-affinity ligand and exists in a conformation that is permanently ready to dimerize with other ligand-bound ErbB receptors like EGFR (Franklin et al., 2004, Cancer Cell). The EGFR-HER2 heterodimer is recognized as the most potent signaling module of the ErbB family, significantly enhancing the duration and intensity of downstream signals compared to homodimers (Graus-Porta et al., 1997, EMBO J). Activation of this complex triggers the Ras-MAPK and PI3K-Akt pathways, which are critical drivers of cell cycle progression, survival, and epithelial-to-mesenchymal transition. Overexpression or co-expression of these receptors is a common feature in several aggressive cancers, including breast, gastric, and non-small cell lung cancer (Baselga et al., 2012, NEJM). Clinically, this heterodimer is a major target for therapeutic intervention, as its formation often contributes to resistance against drugs targeting only one of the receptors. Drugs such as pertuzumab specifically inhibit the formation of this dimer by binding to the extracellular dimerization domain of HER2, while dual tyrosine kinase inhibitors like lapatinib block the intracellular signaling of both components.

Other names

EGFR-ERBB2 complexHER1-HER2 heterodimerErbB1-ErbB2 heterodimerEGFR-HER2 complex

Inhibition of receptor dimerization and competitive or irreversible inhibition of the intracellular tyrosine kinase domain activity.