Epidermal growth factor receptor and Human epidermal growth factor receptor 2 (EGFR and HER2)

Epidermal growth factor receptor (EGFR, also known as ERBB1 or HER1) and human epidermal growth factor receptor 2 (HER2, also known as ERBB2) are members of the ErbB family of receptor tyrosine kinases. These receptors play critical roles in cellular processes such as proliferation, survival, and differentiation via activation of downstream signaling pathways including PI3K/AKT and MAPK. Overexpression or genetic alterations of EGFR and HER2 contribute to tumorigenesis and are associated with poorer prognosis in various cancers, most notably in subsets of breast, lung, and gastric cancers. Lapatinib is a small-molecule, reversible inhibitor that selectively targets the intracellular tyrosine kinase domains of both EGFR and HER2, preventing their phosphorylation and downstream signaling. Dual inhibition with lapatinib can overcome resistance encountered with monoclonal antibodies such as trastuzumab and is clinically used in the management of HER2-positive metastatic breast cancer, especially in combination with other chemotherapeutics such as capecitabine. Relevant biomarkers for drug selection include HER2 amplification and, to a lesser extent, EGFR overexpression. Notable safety issues for targeting these receptors include risks of cardiotoxicity and various on-target toxicities

Other names

Epidermal growth factor receptorERBB1HER1Human epidermal growth factor receptor 2ERBB2HER-2/neu

Inhibition of intracellular ATP-binding site of EGFR/HER2 kinase domains; Blocks receptor phosphorylation, preventing signal transduction via PI3K/AKT and MAPK pathways, leading to reduced cell proliferation and increased apoptosis; Inhibits dimerization and signaling from receptor homo/heterodimers; Possible enhancement of mitochondrial respiration in HER2-positive cells