Abstract
Abstract Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. We and others have previously reported frequent AURKA gene amplification and mRNA and protein overexpression in UGCs. It has been shown that AURKA can induce chemotherapeutic resistance and regulate several key signaling pathways in cancer cells, suggesting its role as a central node in cancer cell signaling. The DCF (docetaxel, cisplatin and 5-FU) regimen is the most promising chemotherapeutic regimen against UGC. However, AURKA overexpression can mediate resistance to both Taxol and cisplatin. These findings provide a credible rationale for targeting AURKA. In this study we have reported therapeutic response of the recently developed AURKA selective inhibitor MLN8237 as a single agent and in combination with docetaxel. Our findings provide a foundation for a promising new approach of future targeted therapy in UGCs. Using AGS, FLO-1 and OE33 UGC cell lines, with constitutive AURKA overexpression and variable-p53 status, we observed inhibition of cancer cell survival with 0.5μM MLN8237 (p<0.05) alone. This effect was significantly enhanced in combination with 1.0nM docetaxel (p<0.001). Cell cycle analyses after 48hr of treatment with MLN8237 demonstrated a significant increase in the percentage of polyploidy for AGS and OE33 UGC cells (p<0.01) which was further enhanced by docetaxel (p<0.001). Additionally, an increase in the percentage of cells in the sub-G1-phase at 24hrs and 48hrs was observed with MLN8237 in FLO-1 (p<0.01) cells which was significantly enhanced with MLN8237 and docetaxel combination (p<0.001). Western blot analysis demonstrated higher induction of cleaved caspase 3 and cleaved PARP with the combined treatment, as compared to a single agent treatment. Using xenograft models, we demonstrated an enhanced anti-tumor role for the MLN8237 and docetaxel combination, as compared to single agent treatments (p<0.001). In conclusion, this study demonstrates that MLN8237, combined with docetaxel, can mediate a better therapeutic outcome in UGCs.
