Pan-Aurora Kinase Inhibitor Mk-0457 Synergistically Potentiates Apo2L/Trail Cytotoxicity in Multiple Mieloma Cells Sensitive and Resistant to Bortezomib.

Abstract 1837 Poster Board I-863 Multiple Myeloma (MM) cells are extremely resistant to apoptosis and currently new potential drug combinations are under investigation. Aurora kinase inhibitors have been shown to abrogate proliferation and induce apoptosis in human myeloma cells lines (HMCLs) and primary myeloma cells. In addition previous studies have shown the antimyeloma activity of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) as a single agent or in combination with certain chemotherapeutic agents. The aim of this study was to investigate whether the combined treatment with pan-Aurora kinase inhibitor MK-0457 also known as VX-680(Vertex/Merck) and Apo2L/TRAIL has cytotoxic effects on MM cells. Because we found that MK-0457 (0.2–0.5 μM) partially activated the extrinsic caspase-8 mediated pathway both in HMCLs RPMI 8226 (highly sensitive to Apo2L/TRAIL: median lethal dose (LD 50 ) at 48 hours was 4.9 ng/mL), and bortezomib-resistant 8226/R5 (barely sensitive to Apo2L/TRAIL: LD 50 at 48 hours was 90.9 ng/mL) we attempted to examine whether MK-0457 potentiates the Apo2L/TRAIL-mediated apoptosis in HMCLs that have differential sensitivity to Apo2L/TRAIL. We first analyzed the pharmacologic interactions between MK-0457 and Apo2L/TRAIL using a fixed-ratio experimental design and found that the combined treatment resulted in the synergistic induction of apoptosis in both HMCLs (Chou-Talalay method): after 48 hours of treatment the averaged Combination Index values calculated from the ED50 (50% effective dose), ED75 and ED90, in MK-0457 plus Apo2L/TRAIL were 0.04 ± 0.05 and 0.03 ± 0.02 in RPMI 8226 and 8226/R5 respectively. Consistent with these results, we found that Aurora-A and -B were expressed at similar levels in RPMI 8226 and 8226/R5 cells and we demonstrated that the functional knock-out of Aurora-A or -B gene expression by small interfering (si)RNAs significantly increased ( P P Disclosures: Lunghi: MERCK sharp and Dohme: Research Funding. Bonati: MERCK sharp and Dohme: Research Funding.