BMS-554417, an inhibitor of the insulin-like growth factor I receptor and insulin receptor, inhibits proliferation and induces mitochondrial pathway-mediated apoptosis in cancer cell lines

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The insulin-like growth factor receptor (IGF1R) and insulin receptor (IR) are overexpressed in many tumor types and contribute to tumorigenicity, proliferation, metastasis and resistance to standard therapies. Here we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF1R, inhibits IGF1R and IR kinase activity, inhibits proliferation in vitro and reduces tumor xenograft growth in vivo. In a series of breast and ovarian cancer cell lines, the IC₅₀ for proliferation ranged from 218 nM (MCF-7) to 8.5 μM (OV202). The sensitivities of tumor cells did not correlate with IGF1R or IR expression or the presence of stimulatory ligands. BMS-554417 treatment inhibited ERK phosphorylation, caused a G₀/G₁ arrest and prevented nuclear accumulation of cyclin D1 in response to the IGF-1 analog, IGF-1 LR3. At doses that inhibited proliferation, the compound also inhibited the PI3k/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser⁴⁷³. Both MCF-7 and OV202 cells treated with BMS-554417 exhibited characteristics of apoptotic cell death, including nuclear fragmentation and cleavage of poly-ADP-ribose polymerase (PARP). To further elucidate whether apoptotic cell death occurred through the intrinsic (mitochondrial) or extrinsic (death receptor) pathways, sensitivity of a series of Jurkat T cell leukemia variants was investigated. In parental Jurkat cells, BMS-554417 induced apoptotic cell morphologic changes at 2.5 μM. However, in Jurkat cells overexpressing Bcl-2 or parental cells treated with a broad spectrum caspase inhibitor, there was no significant induction of apoptosis at the highest dose tested (10 μM). In contrast, loss of caspase 8, a blocking anti-Fas antibody, a synthetic decoy receptor for TRAIL or a caspase 8/10 inhibitor had no effect on the ability of BMS-554417 to induce apoptosis. These data suggest that this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and inhibited the growth of salivary gland tumor xenografts engineered to express constitutively active IGF1R (IGF-1R Sal) in vivo. BMS-554417 is a member of a novel class of IGF1R/IR inhibitors that have potential clinical applications because of their antiproliferative activity in vitro and in vivo. Supported in part by CA15083, CA69008 and the Mayo Foundation.