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Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO‐dependent mechanism
Author(s) -
Kelly Kevin R.,
Nawrocki Steffan T.,
Espitia Claudia M.,
Zhang Mengkun,
Yang Johnny J.,
Padmanabhan Swaminathan,
Ecsedy Jeffrey,
Giles Francis J.,
Carew Jennifer S.
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27579
Subject(s) - cytarabine , aurora inhibitor , clonogenic assay , aurora a kinase , aurora kinase , myeloid leukemia , cancer research , gene knockdown , apoptosis , medicine , pharmacology , aurora b kinase , chemistry , cell , cell cycle , cancer , biochemistry , cell division , spindle apparatus
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.