Novel therapies are urgently needed to improve clinical outcomes for patients 
with acute myeloid leukemia (AML). The investigational drug alisertib (MLN8237) 
is a novel Aurora A kinase inhibitor being studied in multiple Phase I and II 
studies. We investigated the preclinical efficacy and pharmacodynamics of 
alisertib in AML cell lines, primary AML cells and mouse models of AML. Here, we 
report that alisertib disrupted cell viability, diminished clonogenic survival, 
induced expression of the FOXO3a targets p27 and BIM and triggered apoptosis. A 
link between Aurora A expression and sensitivity to ara-C was established, 
suggesting that Aurora A inhibition may be a promising strategy to increase the 
efficacy of ara-C. Accordingly, alisertib significantly potentiated the 
antileukemic activity of ara-C in both AML cell lines and primary blasts. 
Targeted FOXO3a knockdown significantly blunted the pro-apoptotic effects of the 
alisertib/ara-C combination, indicating that it is an important regulator of 
sensitivity to these agents. In vivo studies demonstrated that alisertib 
significantly augmented the efficacy of ara-C without affecting its 
pharmacokinetic profile and led to the induction of p27 and BIM. Our collective 
data indicate that targeting Aurora A with alisertib represents a novel approach 
to increase the efficacy of ara-C that warrants further investigation.