Epidermal growth factor receptor and Erb-B2 receptor tyrosine kinase 3 combination (EGFR/ERBB3)

The combination of Epidermal Growth Factor Receptor (EGFR) and Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3, also known as HER3) represents a critical signaling unit in oncology. While EGFR is a well-characterized oncogenic driver with intrinsic kinase activity, ERBB3 is kinase-impaired and relies on heterodimerization with other ErbB family members, most notably EGFR or HER2, to initiate downstream signaling (Schoeberl et al., 2009). The EGFR/ERBB3 heterodimer is particularly significant because it serves as a powerful activator of the PI3K/AKT survival pathway, which is often implicated in the development of resistance to standard EGFR-targeted therapies (Engelman et al., 2007). In many cancers, such as non-small cell lung cancer (NSCLC), the upregulation or activation of ERBB3 acts as a bypass mechanism that allows tumor cells to survive despite EGFR inhibition (Yonesaka et al., 2011). Consequently, therapeutic strategies targeting both receptors simultaneously—using bispecific antibodies like zenocutuzumab or antibody-drug conjugates like patritumab deruxtecan—are being extensively explored to overcome resistance and improve clinical outcomes in patients with EGFR-mutated or HER3-overexpressing malignancies (Jänne et al., 2022).

Other names

EGFR/HER3 heterodimerHER1/HER3ErbB1/ErbB3EGFR-ERBB3 complex

Simultaneous inhibition of EGFR and ERBB3 signaling to prevent heterodimerization-induced activation of the PI3K/AKT and MAPK pathways, often utilizing bispecific antibodies to block ligand binding or antibody-drug conjugates to deliver cytotoxic payloads to cells expressing these receptors (Schoeberl et al., 2009; Jänne et al., 2022).