Human epidermal growth factor receptor 2 and Human epidermal growth factor receptor 4 (HER2/HER4)

Human epidermal growth factor receptor 2 (HER2) and Human epidermal growth factor receptor 4 (HER4) are transmembrane receptor tyrosine kinases belonging to the ErbB/HER family [1, 2]. HER2 is unique because it lacks a known high-affinity ligand and exists in a constitutively active conformation, making it the preferred heterodimerization partner for other ErbB receptors, which significantly amplifies downstream signaling [1, 5]. HER4 is distinct for its ability to undergo regulated intramembrane proteolysis, releasing an intracellular domain that can translocate to the nucleus to act as a transcriptional co-regulator [2]. These receptors are essential for normal physiological processes, including cardiac and neural development, but their dysregulation is a major driver in several cancers [4, 5]. HER2 amplification is a well-characterized oncogenic driver in breast and gastric cancers, leading to uncontrolled cell proliferation and survival [4]. Therapeutic targeting of both HER2 and HER4, often via pan-HER small molecule inhibitors like neratinib or afatinib, aims to provide a more comprehensive blockade of the ErbB signaling network to overcome resistance mechanisms seen with monospecific agents [3, 5].

Other names

ERBB2 and ERBB4Receptor tyrosine-protein kinase erbB-2 and Receptor tyrosine-protein kinase erbB-4Proto-oncogene NeuCD340p185erbB2HER2/neu

Inhibition of the intracellular tyrosine kinase domain through reversible or irreversible binding to the ATP-binding site, preventing autophosphorylation and downstream signaling cascades such as PI3K/Akt and MAPK/ERK pathways [3, 5].