Receptor tyrosine-protein kinase erbB-2 (ERBB2) (ERBB2)

Receptor tyrosine-protein kinase erbB-2, commonly known as HER2 or ERBB2, is a transmembrane glycoprotein and a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [4, 6, 9]. It plays a pivotal role in cell growth, survival, and differentiation through the activation of downstream signaling pathways such as PI3K/AKT and MAPK/ERK [4, 7, 14]. Unlike other ErbB family members, HER2 does not have a known high-affinity ligand and exists in a constitutively active conformation that allows it to readily heterodimerize with other ligand-bound receptors [4, 6, 14]. The extracellular domain (ECD) of HER2 is a primary target for therapeutic antibodies, which can block its dimerization or induce immune-mediated destruction of the cell [5, 7, 10]. Overexpression or gene amplification of HER2 is a well-characterized oncogenic driver in several cancers, most notably breast and gastric malignancies [1, 6, 15]. Therapeutic agents like trastuzumab and pertuzumab specifically bind to the ECD to inhibit signaling and recruit immune cells via antibody-dependent cellular cytotoxicity (ADCC) [3, 5, 7, 9]. Additionally, antibody-drug conjugates (ADCs) utilize the HER2 receptor for the targeted delivery of potent cytotoxic payloads directly into tumor cells [5, 14]. Despite its therapeutic success, targeting HER2 carries risks such as cardiotoxicity, necessitating careful patient selection and monitoring [1, 2, 10, 13]. Resistance can also occur through the production of truncated forms of the receptor, such as p95HER2, which lack the extracellular domain [3, 15, 19].

Other names

HER2CD340HER-2/neuNEUNGLTKR1Proto-oncogene NeuProto-oncogene c-ErbB-2Metastatic lymph node gene 19 protein

Inhibition of receptor dimerization, induction of antibody-dependent cellular cytotoxicity (ADCC), inhibition of ligand-independent signaling, inhibition of extracellular domain shedding, targeted delivery of cytotoxic payloads, and inhibition of intracellular tyrosine kinase activity.