Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO‐dependent mechanism

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. Acute myeloid leukemia (AML) accounts for 80% of adult acute leukemia. 1 Currently utilized therapeutic agents do not achieve long-term survival for the majority of patients with this disease. Elderly patients with AML have a particularly dismal prognosis with less than 10% achieving long term survival. 2 They are less able to tolerate intensive therapy with cytotoxic agents and they also have a higher prevalence of pre-existing myelodysplasia, unfavorable cytogenetics and multidrug resistance than their younger counterparts. 3 Moreover, a standard induction approach remains to be established for elderly patients with AML due, in part, to the aforementioned factors along with the poor representation of elderly patients in clinical trials. A recent study demonstrated that elderly patients with good or intermediate risk cytogenetics that received therapy with low-dose cytarabine had a significant survival advantage over patients that received supportive care. Despite this, no patients with unfavorable cytogenetics achieved complete responses (CRs) on this study. 4 Furthermore, most elderly patients will not benefit from intensive chemotherapy and have a median survival of less than 6 months with this approach. 5 These poor results underscore the need to develop less toxic targeted therapies based on our understanding of the molecular aberrations in AML to improve clinical outcomes.