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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

Departments of ¹ Medicine and ² Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota; ³ Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey; and ⁴ Adult Leukemia Program, Sidney Kimmel Oncology Center at Johns Hopkins, Baltimore, Maryland

Requests for reprints: Scott H. Kaufmann, Gonda 19-212, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-8950; Fax: 507-284-3906; E-mail: Kaufmann.scott{at}mayo.edu.

Key Words: acute myelogenous leukemia • insulin receptor • insulin-like growth factor receptor • autocrine loop

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. [Cancer Res 2009;69(19):7635–43]