Receptor tyrosine-protein kinase erbB-2 and Receptor tyrosine-protein kinase erbB-4 (ERBB2/ERBB4)

ERBB2 (HER2) and ERBB4 (HER4) are members of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which are essential regulators of cell proliferation, survival, and differentiation (UniProt). ERBB2 is unique as it lacks a known high-affinity ligand and serves as the preferred heterodimerization partner for other ErbB receptors, while ERBB4 is activated by neuregulins and other growth factors (NIH). In oncology, ERBB2 is a well-validated target in breast and gastric cancers, where its overexpression or mutation drives aggressive tumor growth (StatPearls). ERBB4's role is more complex, acting as either a tumor suppressor or an oncogene depending on the cellular context and isoform expression (PubMed). Crucially, the ERBB2/ERBB4 heterodimer is vital for cardiac homeostasis and development, particularly in maintaining cardiomyocyte survival (Frontiers in Physiology). Consequently, pharmacological inhibition of these receptors by pan-ErbB inhibitors like neratinib or afatinib can lead to cardiotoxicity as a significant side effect (NIH). Therapeutic strategies include monoclonal antibodies that block dimerization and small-molecule tyrosine kinase inhibitors (TKIs) that provide broad inhibition across the ErbB family (PubMed).

Other names

HER2HER4NEUCD340p180erbB4ERBB2ERBB4Human epidermal growth factor receptor 2Human epidermal growth factor receptor 4HER2/HER4 complexErbB2-ErbB4 heterodimer

Drugs targeting ERBB2 and ERBB4 primarily act through the inhibition of the intracellular tyrosine kinase domain, preventing the phosphorylation of downstream signaling molecules in the PI3K/Akt and MAPK/ERK pathways. Small-molecule inhibitors like neratinib and afatinib are often irreversible binders that target the ATP-binding site of the kinase. Monoclonal antibodies such as trastuzumab and pertuzumab bind to the extracellular domains of ERBB2 to inhibit ligand-independent signaling, prevent receptor dimerization, and induce antibody-dependent cellular cytotoxicity (ADCC).