Epidermal growth factor receptor–Receptor tyrosine-protein kinase erbB-3 interface (EGFR–HER3 interface) (EGFR–HER3 interface)

The Epidermal growth factor receptor (EGFR)–Receptor tyrosine-protein kinase erbB-3 (HER3) interface is a critical protein-protein interaction site involved in the formation of oncogenic heterodimers within the ErbB receptor family [1, 2]. While EGFR is a well-characterized receptor tyrosine kinase with strong intrinsic activity, HER3 possesses a deficient kinase domain and must heterodimerize with other family members, most notably EGFR or HER2, to initiate robust intracellular signaling [2, 3]. The EGFR–HER3 complex is recognized as one of the most potent activators of the phosphoinositide 3-kinase (PI3K)/Akt survival pathway, which drives tumor growth and confers resistance to apoptosis [3, 4]. In many malignancies, including non-small cell lung cancer and colorectal cancer, the formation of this heterodimer serves as a primary mechanism of acquired resistance to standard EGFR-targeted monotherapies [4, 5]. Therapeutic strategies targeting this interface, such as bispecific antibodies like duligotuzumab, are designed to simultaneously block ligand binding and the physical association between the two receptors [5, 6]. By disrupting this specific interface, these agents aim to suppress bypass signaling and overcome the therapeutic limitations of targeting either receptor in isolation [6]. Sources: [1] UniProt (P00533, P21860) [2] Hynes, N. E., & Lane, H. A. (2005). Nature Reviews Cancer [3] Sithanandam, G., & Kolch, W. (2008). Cancer Letters [4] Wheeler, D. L., et al. (2008). Oncogene [5] Schaefer, G., et al. (2011). Cancer Cell [6] ClinicalTrials.gov (NCT01207388)

Other names

EGFR/HER3 heterodimerErbB1/ErbB3 interfaceEGFR-ErbB3 complexEpidermal growth factor receptor/Human epidermal growth factor receptor 3 interface

Inhibition of EGFR and HER3 heterodimerization and ligand binding (such as Neuregulin-1 or EGF), thereby preventing the activation of downstream oncogenic pathways like PI3K/Akt and MAPK/ERK [5, 6].