p95 Human epidermal growth factor receptor 2 (p95 HER2)

p95 HER2 refers to a group of truncated isoforms of the Human Epidermal Growth Factor Receptor 2 (HER2) that lack the extracellular domain (ECD) [1, 18]. These fragments, primarily the 611-CTF and 678-CTF, are generated through either proteolytic shedding of the ECD by metalloproteinases or alternative initiation of translation from internal mRNA codons [10, 16]. Because they lack the ECD, p95 HER2 fragments are inherently resistant to monoclonal antibodies like trastuzumab and pertuzumab, which require the ECD for binding [3, 4]. However, they retain a constitutively active intracellular tyrosine kinase domain that drives aggressive tumor growth and survival through the PI3K/AKT and MAPK signaling pathways [5, 7]. p95 HER2 is found in approximately 30-40% of HER2-positive breast cancers and serves as a biomarker for poor prognosis and resistance to standard HER2-targeted therapies [1, 19]. Therapeutic strategies to address this target include small-molecule tyrosine kinase inhibitors (TKIs) like lapatinib and neratinib, which can penetrate the cell to inhibit the kinase domain, as well as novel agents like p95HER2-specific bispecific antibodies that target epitopes exposed only on the truncated fragment [12, 15]. Recent research also indicates that p95 HER2 promotes an immunosuppressive tumor microenvironment by upregulating PD-L1 and interleukin-6, further contributing to treatment resistance [9, 11].

Other names

p95HER2HER2 carboxy-terminal fragmentsCTF611-CTF678-CTFTruncated HER2 receptorHER2-CTF

Tyrosine kinase inhibition, HSP90 inhibition, T-cell redirection, and immune checkpoint modulation.