Long-sought elusive LIGAND of her2 found& its derivative may be the best treatment 4

[Lani]

her2+ bc yet(so far results only in mice), may be combined with herceptina/pertuzumab and should be cheap to produce (by bacteria)

free open access

EBioMedicine. 2015 May 1;2(5):396-405.


Inhibition of ERBB2-overexpressing Tumors by Recombinant Human Prolidase and Its Enzymatically Inactive Mutant.
Yang L1, Li Y2, Bhattacharya A1, Zhang Y1.

Author information
1Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.
2Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY 14263, United States ; Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, Unites States.


Abstract
ERBB2 is an oncogenic receptor tyrosine kinase overexpressed in a subset of human breast cancer and other cancers. We recently found that human prolidase (PEPD), a dipeptidase, is a high affinity ERBB2 ligand and cross-links two ERBB2 monomers. Here, we show that recombinant human PEPD (rhPEPD) strongly inhibits ERBB2-overexpressing tumors in mice, whereas it does not impact tumors without ERBB2 overexpression. rhPEPD causes ERBB2 depletion, disrupts oncogenic signaling orchestrated by ERBB2 homodimers and heterodimers, and induces apoptosis. The impact of enzymatically-inactive mutant rhPEPDG278D on ERBB2 is indistinguishable from that of rhPEPD, but rhPEPDG278D is superior to rhPEPD for tumor inhibition. The enzymatic function of rhPEPD stimulates HIF-1α and other pro-survival factors in tumors, which likely attenuates its antitumor activity. rhPEPDG278D is also attractive in that it may not interfere with the physiologic function of endogenous PEPD in normal cells. Collectively, we have identified a human protein as an inhibitory ERBB2 ligand that inhibits ERBB2-overexpressing tumors in vivo. Several anti-ERBB2 agents are on the market but are hampered by drug resistance and high drug cost. rhPEPDG278D may synergize with these agents and may also be highly cost-effective, since it targets ERBB2 with a different mechanism and can be produced in bacteria.
KEYWORDS:
ERBB2; ERBB2 ligand; PEPD; anti-ERBB2 agent; prolidase
PMID: 26086037