Epidermal growth factor receptor–ErbB3 signaling axis (EGFR–ErbB3)

The Epidermal growth factor receptor (EGFR)–ErbB3 signaling axis is a critical regulatory unit within the ErbB family of receptor tyrosine kinases, primarily responsible for driving cell growth, survival, and metabolism (Source: UniProt P00533, P21860). While EGFR (ErbB1) possesses strong intrinsic kinase activity, ErbB3 (HER3) is characterized by a nearly inactive pseudokinase domain and must heterodimerize with other family members, such as EGFR, to initiate downstream signaling (Source: PubMed PMID: 24510949). This heterodimer is exceptionally potent because ErbB3 contains six docking sites for the p85 subunit of PI3K, making the EGFR–ErbB3 complex a primary driver of the PI3K/Akt/mTOR survival pathway. In oncology, this axis is a major mediator of resistance to EGFR-targeted tyrosine kinase inhibitors (TKIs), as tumors often upregulate ErbB3 or its ligand, neuregulin-1 (NRG1), to maintain signaling despite EGFR blockade (Source: PubMed PMID: 32814731). Therapeutic interventions targeting this axis include pan-ErbB inhibitors like afatinib, bispecific antibodies like zenocutuzumab, and antibody-drug conjugates such as patritumab deruxtecan. Clinical challenges associated with targeting this axis include managing gastrointestinal and dermatological toxicities, as well as overcoming complex feedback loops that can lead to further drug resistance. Monitoring for biomarkers such as NRG1 fusions or HER3 overexpression is essential for identifying patients most likely to benefit from these targeted therapies.

Other names

HER1–HER3 axisEGFR–HER3 heterodimerErbB1–ErbB3 signaling pathwayEGFR–ErbB3 complex

The axis is targeted through small-molecule inhibition of the EGFR kinase domain, monoclonal antibodies that block ligand binding or receptor dimerization, and antibody-drug conjugates that utilize HER3 or EGFR expression for selective cytotoxic delivery.