title: 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.
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.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27384, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Bertrand
authors.forename: L S
authors.initials: LS
authors.lastname: Steelman
authors.forename: W H
authors.initials: WH
authors.lastname: Chappell
authors.forename: S L
authors.initials: SL
authors.lastname: Abrams
authors.forename: J G
authors.initials: JG
authors.lastname: Shelton
authors.forename: E R
authors.initials: ER
authors.lastname: White
authors.forename: D L
authors.initials: DL
authors.lastname: Ludwig
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D007167:Immunotherapy; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007938:Leukemia / Q000628:therapy; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000276:immunology* / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; C546843:mTOR protein, mouse