Abstract
14069 Background: MK-0457 (VX-680) is a reversible kinase inhibitor that targets Aurora A, B and C (Ki’s of 0.7, 18 and 4.6 nM, respectively). Clinical trials are on-going in patients with solid tumors and hematologic malignancies. This study evaluated the in vitro combination of MK-0457 and Taxotere (TXT) to determine if inhibition of Aurora kinases, which are critical for cytokinesis and spindle assembly may synergize with a microtubule targeted agent. Methods: A panel of cancer cell lines (that were either wild-type, mutant, or null for p53) and a matched pair of A549 cell lines either expressing p53 shRNA or vector control (A549p53- and A549p53+) were evaluated for sensitivity to MK-0457 and/or TXT. Viability was measured by Cell Titer Glo (Promega). Cell cycle profiles were determined by FACS analysis, and colony formation (CFU) assays were performed in soft agar and on plastic. Combination effects were evaluated by the Bliss Independence method. Results: Single agent IC50’s ranged from 50 nM to > 5 μM for MK-0457 and 0.4 to 10 nM for TXT. FACS analysis of DNA content showed MK-0457 induced G2/M arrest and polyploidy, characteristic of Aurora kinase inhibition. The effects of MK-0457 and TXT combination ranged from antagonism to synergy and were concentration, cell context, and regimen dependent. In 3–4 day viability assays simultaneous combination of MK-0457 + TXT did not show synergy, however sequential exposure showed synergy at low concentrations of both agents. In contrast to the short-term viability assays, simultaneous exposure to MK-0457 + TXT in long term survival assays (i.e. CFU on plastic or soft agar) resulted in enhanced cell death compared to the single agents. Conclusions: The synergy observed for MK-0457 + TXT, especially in long term survival assays, supported the evaluation of this combination in xenograft models (described in B. Furey et al., ASCO 2006). No significant financial relationships to disclose.
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