In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417

Paul Haluska, Joan M. Carboni, David A. Loegering, Francis Y. Lee, Mark Wittman, Mark G. Saulnier, David B. Frennesson, Kimberly R. Kalli, Cheryl A. Conover, Ricardo M. Attar, Scott H. Kaufmann, Marco Gottardis, Charles Erlichman

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160 Scopus citations

Abstract

The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 μmol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser 473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)362-371
Number of pages10
JournalCancer research
Volume66
Issue number1
DOIs
StatePublished - Jan 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Haluska, P., Carboni, J. M., Loegering, D. A., Lee, F. Y., Wittman, M., Saulnier, M. G., Frennesson, D. B., Kalli, K. R., Conover, C. A., Attar, R. M., Kaufmann, S. H., Gottardis, M., & Erlichman, C. (2006). In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer research, 66(1), 362-371. https://doi.org/10.1158/0008-5472.CAN-05-1107