Human epidermal growth factor receptor 2 (HER2) and p95HER2 (HER2 / p95HER2)

Human epidermal growth factor receptor 2 (HER2), also known as ERBB2, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [1]. Unlike other members of its family, HER2 has no known high-affinity ligand and exists in a constitutively active conformation, which allows it to readily heterodimerize with other ErbB receptors to trigger potent downstream signaling via the PI3K/Akt and MAPK pathways [2]. p95HER2 refers to a group of truncated carboxy-terminal fragments of the HER2 receptor that lack the extracellular domain (ECD) [3]. These fragments can be generated through the proteolytic shedding of the ECD by metalloproteases or through the alternative initiation of translation from internal codons [4]. Because p95HER2 lacks the extracellular binding site for the monoclonal antibody trastuzumab, its presence in tumor cells is a well-documented mechanism of therapeutic resistance [3, 5]. However, since p95HER2 retains its intracellular kinase domain, it remains a target for small-molecule tyrosine kinase inhibitors (TKIs) such as lapatinib and neratinib [5]. HER2 overexpression or gene amplification is found in approximately 15-20% of breast cancers and is also a key driver in gastric and esophageal cancers, where it serves as a critical therapeutic target and prognostic biomarker [6].

Other names

ERBB2CD340Proto-oncogene Neup185HER2Truncated HER2 receptorHER2 carboxy-terminal fragments (CTF)

Inhibition of receptor dimerization, inhibition of intracellular tyrosine kinase activity, induction of antibody-dependent cellular cytotoxicity (ADCC), inhibition of extracellular domain shedding, and induction of receptor internalization and degradation [1, 2, 5].