Small Molecule Therapeutics HER2-Targeted Hybrid Peptide That Blocks HER2 Tyrosine Kinase Disintegrates Cancer Cell Membrane and Inhibits Tumor Growth In Vivo

HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20% to 30% of breast cancers. We have recently designed a novel class of drug, the hybrid peptide, which is chemically synthesized and is composed of a target-binding peptide and a lytic peptide containing cationic-rich amino acid components that disintegrate the cell membrane, leading to cancer cell death via membrane lysis. In this study,wedesignedaHER2-bindingpeptide linked to this novel lytic peptide,whichwe termed the HER2-lytic hybrid peptide and assessed the cytotoxic activity of this hybrid peptide in vitro and in vivo. The HER2-lytic hybrid peptide showed high cytotoxic activity against all ovarian and breast cancer cell lines, even trastuzumaband/or lapatinib-resistant cells, but not against normal cells. Competition assays using anti-HER2 antibody and knockdown of this receptor by siRNA confirmed the specificity of the HER2lytic hybrid peptide. In addition, it was shown that the HER2-lytic hybrid peptide can disintegrate the cancer cell membrane of HER2-overexpressing SK-BR-3 cancer cells in only 5minutes, but not normal cells, and block HER2 signaling. Intravenous administration of the HER2-lytic peptide in the athymic mouse implanted with BT-474 and MDA-MB-453 cells significantly inhibited tumor progression. The HER2-lytic hybrid peptide was effective even in breast cancer cell lines that are resistant to trastuzumab and/or lapatinib in vitro and in vivo. Therefore, this hybrid peptidemay provide a potent treatment option for patients with cancer.Mol Cancer Ther; 12(4); 384–93. 2013 AACR.