title: A bifunctional targeted peptide that blocks HER-2 tyrosine kinase and disables mitochondrial function in HER-2-positive carcinoma cells.
abstract: The HER-2 oncoprotein is commonly overexpressed in a variety of human malignancies and has become an attractive antitumor target. A number of strategies to inhibit the HER-2 receptor tyrosine kinase are currently the focus of intensive preclinical and clinical research. In the present study, we have engineered a bifunctional peptide, BHAP, which consists of two modular domains: a HER-2-targeting/neutralizing domain and a mitochondriotoxic, proapoptotic domain. The chimeric peptide is biologically active and capable of selectively triggering apoptosis of HER-2-overexpressing cancer cells in culture, even those previously described as Herceptin resistant. Furthermore, BHAP slows down growth of HER-2-overexpressing human mammary xenografts established in SCID mice. This approach can be extended to the development of tailored targeted chimeric peptides against a number of overexpressed cellular receptors implicated in the development and progression of cancer.
authors.affiliation: Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02215, USA. vfantin@genetics.med.harvard.edu
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Berardi
authors.forename: Holger
authors.initials: H
authors.lastname: Babbe
authors.forename: Montserrat V
authors.initials: MV
authors.lastname: Michelman
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Manning
authors.forename: Philip
authors.initials: P
authors.lastname: Leder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins