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.
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.
Departments of Medicine and Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Andrea E
AE
Wahner Hendrickson
Paul
P
Haluska
Paula A
PA
Schneider
David A
DA
Loegering
Kevin L
KL
Peterson
Ricardo
R
Attar
B Douglas
BD
Smith
Charles
C
Erlichman
Marco
M
Gottardis
Judith E
JE
Karp
Joan M
JM
Carboni
Scott H
SH
Kaufmann
D001562:Benzimidazoles / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020298:U937 Cells
C504983:BMS 536924; D001562:Benzimidazoles; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin