Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: Effect of the dual-receptor inhibitor BMS-536924 in vitro

Andrea E.Wahner Hendrickson, Paul Haluska, Paula A. Schneider, David A. Loegering, Kevin L. Peterson, Ricardo Attar, B. Douglas Smith, Charles Erlichman, Marco Gottardis, Judith E. Karp, Joan M. Carboni, Scott H. Kaufmann

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are receptor tyrosine kinases that participate in mitogenic and antiapoptotic signaling in normal and neoplastic epithelia. In the present study, immunoblotting and reverse transcription-PCR demonstrated expression of IGF1R and IR isoform A in acute myelogenous leukemia (AML) cell lines as well as in >80% of clinical AML isolates. Treatment with insulin enhanced signaling through the Akt and MEK1/2 pathways as well as survival of serum-starved AML cell lines. Conversely, treatment with BMS-536924, a dual IGF1R/IR kinase inhibitor that is undergoing preclinical testing, inhibited constitutive receptor phosphorylation as well as downstream signaling through MEK1/2 and Akt. These changes inhibited proliferation and, in some AML cell lines, induced apoptosis at submicromolar concentrations. Likewise, BMS-536924 inhibited leukemic colony formation in CD34+ clinical AML samples in vitro. Collectively, these results not only indicate that expression of IGF1R and IR isoform A is common in AML but also show that interruption of signaling from these receptors inhibits proliferation in clinical AML isolates. Accordingly, further investigation of IGF1R/IR axis as a potential therapeutic target in AML appears warranted.

Original languageEnglish (US)
Pages (from-to)7635-7643
Number of pages9
JournalCancer research
Volume69
Issue number19
DOIs
StatePublished - Oct 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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