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

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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