Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo.
Clinical studies indicate that Herceptin (trastuzumab), a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2) tyrosine kinase growth factor receptor, provides a significant but transient survival advantage to a subset of patients with HER-2-overexpressing metastatic breast cancer when given as a first-line agent. Increased insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has recently been identified as a potential factor adversely influencing the response to Herceptin. We examined the effect of recombinant human IGF binding protein 3 (rhIGFBP-3), an antagonist of IGF-IR signaling, in Herceptin-resistant breast cells in vitro and in tumors in vivo. Consistent with results obtained using HER-2- or IGF-IR-transfected cells (MCF-7/HER2-18 and SKBR3/IGF-IR, respectively), we found that rhIGFBP-3 significantly reduced IGF-I-induced IGF-IR phosphorylation and displayed a synergistic interaction with Herceptin against cultured HER-2-overexpressing breast cancer cells in vitro. We show, for the first time, the antitumor activity of rhIGFBP-3 against advanced-stage MCF-7/HER2-18-transfected human breast cancer xenografts and its potentiation of Herceptin activity. We also provide evidence that IGF-IR activation counters the early suppressive effect of Herceptin on HER-2 signaling via Akt and p44/p42 mitogen-activated protein kinase (MAPK), and that inhibition of HER-2-overexpressing human breast tumor growth by rhIGFBP-3 is associated with restored down-regulation of Akt and p44/p42 MAPK phosphorylation in vitro and in vivo. These results emphasize the merit of evaluating simultaneous blockade of the HER-2 and IGF-IR pathways using combination therapy with rhIGFBP-3 plus Herceptin in human clinical trials of patients with HER-2-positive breast cancer.
Jerome
Lori
L
Department of Oncology, McGill University, West, Montreal, Quebec, Canada.
Alami
Nezha
N
Belanger
Sylvie
S
Page
Viviane
V
Yu
Qingnan
Q
Paterson
Jesse
J
Shiry
Laura
L
Pegram
Mark
M
Leyland-Jones
Brian
B
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000096:biosynthesis*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D018972:Insulin-Like Growth Factor Binding Protein 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011994:Recombinant Proteins; D000068878:Trastuzumab; C508053:ERBB2 protein, human