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Signal Transduction and Cytokines

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 volume 20, pages 1254–1260 (2006)Cite this article

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 αIGF-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.

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Acknowledgements

This work was supported by NCI Grant RO1 CA098195 (JAM).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    F E Bertrand, L S Steelman, W H Chappell, S L Abrams, J G Shelton, E R White & J A McCubrey

  2. ImClone Systems Incorporated, New York, NY, USA

    D L Ludwig

  3. Leo Jenkins Cancer Center, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    J A McCubrey

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  1. F E Bertrand
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  2. L S Steelman
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  3. W H Chappell
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  4. S L Abrams
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  5. J G Shelton
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  6. E R White
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  7. D L Ludwig
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Correspondence to J A McCubrey.

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Bertrand, F., Steelman, L., Chappell, W. et al. 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 20, 1254–1260 (2006). https://doi.org/10.1038/sj.leu.2404217

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  • DOI: https://doi.org/10.1038/sj.leu.2404217

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