ERBB3 (also known as HER3) is a member of the ERBB receptor tyrosine kinase family, which includes EGFR (HER1), HER2. and HER4. Unlike other family members, ERBB3 has impaired kinase activity due to structural variations in its kinase domain, necessitating heterodimerization with other ERBB receptors (e.g., HER2) for downstream signaling. ERBB3 plays a critical role in regulating cell proliferation, survival, and differentiation via activation of key pathways like PI3K/AKT and MAPK. Its overexpression or aberrant activation is implicated in various cancers, including breast, lung, and colorectal, often contributing to tumor progression, metastasis, and resistance to targeted therapies (e.g., EGFR or HER2 inhibitors).
ERBB3-targeted antibodies are designed to block these oncogenic signals. Monoclonal antibodies (e.g., patritumab, seribantumab) bind to ERBB3’s extracellular domain, preventing ligand binding (e.g., neuregulins) or receptor dimerization, thereby inhibiting downstream signaling. Some antibodies also promote receptor internalization and degradation. Additionally, antibody-drug conjugates (ADCs) and bispecific antibodies (targeting ERBB3 and other ERBB members) are under investigation to enhance therapeutic efficacy. Challenges include identifying predictive biomarkers and overcoming compensatory signaling mechanisms. Clinical trials have shown mixed results, highlighting the need for patient stratification and combination strategies. Overall, ERBB3 antibodies represent a promising approach to tackle resistance in ERBB-driven cancers.