Human epidermal growth factor receptor 3 and 4 (HER3/HER4)

Human epidermal growth factor receptor 3 (HER3/ErbB3) and 4 (HER4/ErbB4) are members of the ErbB family of receptor tyrosine kinases, which play critical roles in regulating cell growth, survival, and differentiation. HER3 is unique as it possesses a catalytically inactive pseudokinase domain and must heterodimerize with other family members, such as HER2 or HER4, to initiate potent signaling via the PI3K/Akt pathway. HER4 is a fully functional kinase that can also undergo regulated intramembrane proteolysis to release an intracellular domain that translocates to the nucleus to regulate gene expression. In oncology, HER3 is frequently overexpressed or mutated, serving as a major mechanism of resistance to other HER-targeted therapies, while HER4 has a more complex role, acting as either an oncogene or a tumor suppressor depending on the tissue context. Therapeutic strategies targeting these receptors include pan-HER tyrosine kinase inhibitors, bispecific antibodies that prevent dimerization, and antibody-drug conjugates designed to deliver cytotoxic payloads directly to overexpressing tumor cells.

Other names

ErbB3/ErbB4Receptor tyrosine-protein kinase erbB-3/erbB-4HER3/4ErbB-3/ErbB-4

Inhibition of receptor dimerization, blockade of ligand binding, and irreversible or reversible inhibition of the intracellular tyrosine kinase domain to prevent downstream signaling cascades.