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.

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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 19 Pg. 7635-43 (Oct 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19789352 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BMS 536924
• Benzimidazoles
• Protein Isoforms
• Protein Kinase Inhibitors
• Pyridones
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Receptor, Insulin

Topics

• Benzimidazoles (pharmacology)
• Cell Growth Processes (drug effects, physiology)
• HL-60 Cells
• Humans
• Insulin-Like Growth Factor I (biosynthesis)
• K562 Cells
• Leukemia, Myeloid, Acute (drug therapy, enzymology, pathology)
• Protein Isoforms
• Protein Kinase Inhibitors (pharmacology)
• Pyridones (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, biosynthesis)
• Receptor, Insulin (antagonists & inhibitors, biosynthesis)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• U937 Cells