Truncated human epidermal growth factor receptor 2 (p95HER2)

p95HER2 refers to a group of N-terminally truncated fragments of the human epidermal growth factor receptor 2 (HER2/ErbB2) that lack the extracellular domain (ECD) but retain the transmembrane and intracellular kinase domains [1, 3]. These fragments are generated either through proteolytic shedding of the HER2 ECD by metalloproteases such as ADAM10 or via alternative initiation of translation from internal codons, most notably at position 611 (611-CTF) [1, 12]. Because they lack the binding site for monoclonal antibodies like trastuzumab and pertuzumab, p95HER2-expressing tumors are inherently resistant to these standard-of-care therapies [3, 6, 10]. However, p95HER2 remains constitutively active, forming homodimers that drive aggressive oncogenic signaling through the PI3K/AKT and MAPK pathways, leading to poor clinical outcomes and increased metastatic potential [1, 5, 14]. Unlike full-length HER2, which is expressed at low levels in some normal tissues, p95HER2 is considered a tumor-specific antigen as it is not detected in normal adult human tissues [11, 12]. This specificity makes it an ideal target for novel therapeutic modalities, including small-molecule tyrosine kinase inhibitors (TKIs) like lapatinib and neratinib, which act on the intracellular domain, and investigational T-cell bispecific antibodies (TCBs) that selectively recruit the immune system to tumor cells while sparing healthy tissue [8, 9, 21]. Recent research also highlights the role of p95HER2 in promoting an immunosuppressive tumor microenvironment by upregulating PD-L1 and IL-6, further emphasizing its importance as both a biomarker for patient stratification and a target for overcoming therapy resistance [7, 9].

Other names

p95HER2 carboxy-terminal fragment611-CTF678-CTF648-CTFTruncated ErbB2HER2-CTF

Inhibition of the intracellular tyrosine kinase domain, induction of proteasomal degradation, and T-cell mediated cytotoxicity via bispecific recruitment.