Grb2-SH3 ligand inhibits the growth of HER2+ cancer cells and has antitumor effects in human cancer xenografts alone and in combination with docetaxel.
HER2 represents an important signaling pathway in breast and other cancers. Herceptin has demonstrated clinical activity, but resistance is common. Thus, new therapeutic approaches to the HER2 pathway are needed. Grb2 is an adaptor protein involved in Ras-dependent signaling induced by HER2 receptors. A specific Grb2-SH3 ligand, designed and synthesized in our laboratory, called peptidimer-c, inhibited colony formation in HER2 overexpressing SKBr3 cancer cells. Combined treatment of peptidimer-c with docetaxel further inhibited both colony formation and tumor cell survival compared to docetaxel treatment alone. Efficacy of this combined treatment was correlated with a reduction in the phosphorylation of MAPK and AKT. Finally, peptidimer-c reduced the growth of a HER2(+) human breast cancer (BK111) xenograft in nude mice and potentiated the antitumor effect of docetaxel in a HER2+ hormone-independent human prostate adenocarcinoma (PAC120 HID28) xenograft. These results validate Grb2 as a new target for the HER2 pathway.
Gril
Brunilde
B
Université Paris Descartes, UFR Biomédicale, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, Paris, France.
Vidal
Michel
M
Assayag
Franck
F
Poupon
Marie-France
MF
Liu
Wang-Qing
WQ
Garbay
Christiane
C
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains
D000970:Antineoplastic Agents; D000077143:Docetaxel; D051380:GRB2 Adaptor Protein; D008024:Ligands; D009842:Oligopeptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; C495948:GRB2 protein, human