BACKGROUND: Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to 
current chemotherapeutic regimes. The authors and others have previously 
reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and 
protein overexpression in UGCs. The objective of the current study was to 
determine the therapeutic potential of alisertib (MLN8237) alone and in 
combination with docetaxel in UGCs.
METHODS: After treatment with alisertib and/or docetaxel, clonogenic cell 
survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth 
assays were carried out to measure cell survival, cell cycle progression, 
apoptotic protein expression, and tumor xenograft volumes, respectively.
RESULTS: By using the AGS, FLO-1, and OE33 UGC cell lines, which have 
constitutive AURKA overexpression and variable tumor protein 53 (p53) status, 
significantly enhanced inhibition of cancer cell survival was observed with 
alisertib and docetaxel treatment in combination (P < .001), compared with 
single-agent treatments. Cell cycle analyses, after 48 hours of treatment with 
alisertib, produced a significant increase in the percentage of polyploidy in 
UGC cells (P < .01) that was further enhanced by docetaxel (P < .001). In 
addition, an increase in the percentage of cells in sub-G1-phase observed with 
alisertib (P < .01) was significantly enhanced with the combination treatment (P 
< .001). Western blot analysis demonstrated higher induction of cleaved caspase 
3 protein expression with the combined treatment compared with single-agent 
treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated 
enhanced antitumor activity for the alisertib and docetaxel combination compared 
with single-agent treatments (P < .001).
CONCLUSIONS: The current study demonstrated that alisertib combined with 
docetaxel can mediate a better therapeutic outcome in UGC cell lines.