ErbB receptor tyrosine kinase family (ErbB family)

The ErbB family of receptor tyrosine kinases, specifically comprising Epidermal Growth Factor Receptor (EGFR/ErbB1), Human Epidermal Growth Factor Receptor 2 (HER2/ErbB2), and Human Epidermal Growth Factor Receptor 4 (HER4/ErbB4), are critical mediators of cell growth, survival, and differentiation. These transmembrane proteins are activated through ligand-induced dimerization (or ligand-independent dimerization in the case of HER2), which triggers the phosphorylation of intracellular tyrosine residues and initiates downstream signaling cascades like the PI3K/Akt and MAPK pathways. Dysregulation of these kinases through gene amplification, protein overexpression, or activating mutations is a hallmark of many solid tumors, including breast, lung, and gastric cancers. Therapeutic intervention often involves small-molecule tyrosine kinase inhibitors (TKIs) that target the ATP-binding pocket of the kinase domain. While first-generation inhibitors were often selective for one or two members, second-generation 'pan-ErbB' inhibitors like afatinib and neratinib provide irreversible, multi-target inhibition to overcome resistance and achieve more potent anti-tumor activity. However, because these receptors are also expressed in normal epithelial tissues, their inhibition is frequently associated with on-target toxicities such as severe diarrhea and dermatological reactions.

Other names

HER familyEpidermal growth factor receptor familyEGFR/HER2/HER4 tyrosine kinasesType I receptor tyrosine kinase family

Inhibition of the intracellular tyrosine kinase domain by competing with ATP for binding, leading to the blockade of autophosphorylation and downstream signaling pathways such as MAPK/ERK and PI3K/Akt/mTOR.