Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells

Leukemia. 2006 Jul;20(7):1254-60. doi: 10.1038/sj.leu.2404217. Epub 2006 Apr 27.

Abstract

The Insulin-like growth factor-1 receptor (IGF-1R) is overexpressed in a variety of tumors including breast, prostate and myeloma. Thus, IGF-1R and its downstream signaling effectors are good candidates for molecular-based targeted antitumor therapies. Indeed, protein inhibitors of IGF-1R signaling and IGF-1R blocking antibodies are undergoing clinical trials. Herein, the molecular basis for antibody-mediated IGF-1R signal inhibition has been investigated in a hematopoietic cell line model, FDC-P1, that has been rendered interleukin-3 independent in a ligand-dependent manner through retroviral-mediated expression of IGF-1R (FD/IGF-1R). Furthermore, the ability of an anti-IGF-1R antibody to synergize with signal-transduction pathway inhibitors and induce apoptosis was determined. The alphaIGF-1R antibody, A12, was capable of arresting IGF-1 or insulin-induced FD/IGF-1R cell proliferation in the G1 phase of the cell cycle and resulted in apoptotic induction. A12 effectiveness could be potentiated through combination treatment with small molecule inhibitors of the Ras/Raf/MEK/ERK or PI3K/Akt/mTOR pathways. These results validate the use of the FD/IGF-1R cells to evaluate the effectiveness and mechanisms of targeted IGF-1R therapeutic strategies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibody Specificity
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line, Transformed
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • G1 Phase / drug effects
  • G1 Phase / physiology
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / enzymology
  • Immunotherapy
  • Insulin-Like Growth Factor I / pharmacology
  • Leukemia / therapy
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / immunology*
  • Receptor, IGF Type 1 / metabolism*
  • S Phase / drug effects
  • S Phase / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases
  • raf Kinases / metabolism

Substances

  • Antibodies, Monoclonal
  • Enzyme Inhibitors
  • Insulin-Like Growth Factor I
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases