Human epidermal growth factor receptor 2, methionine 611 carboxy-terminal fragment (p95HER2)

p95HER2 refers to a group of amino-terminally truncated fragments of the HER2 receptor, most notably the methionine 611 carboxy-terminal fragment (Met611–p95)[1][2][7]. These truncated receptors lack the extracellular ligand-binding and trastuzumab-binding domains but retain an intact intracellular tyrosine kinase domain, resulting in constitutive, ligand-independent activation of HER2 signaling pathways[1][2]. p95HER2 arises by either proteolytic shedding of full-length HER2 or by translation from internal HER2 mRNA initiation sites[1]. Approximately 40–50% of HER2-positive breast cancers express p95HER2, which is consistently associated with poor prognosis, increased tumor aggressiveness, and resistance to trastuzumab therapy[1][4][5]. However, p95HER2-expressing cells retain sensitivity to certain small-molecule kinase inhibitors (e.g., lapatinib) and are a current focus for therapies such as p95HER2–directed bispecific T cell–engaging antibodies, which show enhanced tumor specificity due to lack of p95HER2 expression in normal tissues[4]. p95HER2 can serve as a biomarker for predicting resistance to anti-HER2 monoclonal antibodies and poorer outcomes in breast cancer; its detection is now feasible by specialized immunoassays and quantitative platforms like VeraTag[2][5]. Safety challenges in targeting p95HER2 include avoiding off-target effects and overcoming resistance mechanisms inherent to truncated HER2 signaling[1][2][4].

Other names

p95HER2/611 carboxy terminal fragmentp110HER2 C-terminal fragmentHER2-CTFtruncated HER2Met611–p95

Tyrosine kinase inhibition (e.g., by lapatinib); T cell recruitment and cytotoxicity (by bispecific antibodies)