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A Bifunctional Targeted Peptide that Blocks HER-2 Tyrosine Kinase and Disables Mitochondrial Function in HER-2-Positive Carcinoma Cells

¹ Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute and ² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Valeria R. Fantin, Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Room 356, New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02215. Phone: 617-432-7578; E-mail: vfantin{at}genetics.med.harvard.edu.

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.

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