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

Kevin R. Kelly, Steffan T. Nawrocki, Claudia M. Espitia, Mengkun Zhang, Johnny J. Yang, Swaminathan Padmanabhan, Jeffrey Ecsedy, Francis J. Giles, Jennifer S. Carew

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2693-2703
Number of pages11
JournalInternational Journal of Cancer
Volume131
Issue number11
DOIs
StatePublished - Dec 1 2012

Keywords

  • Aurora kinase A
  • FOXO
  • acute myeloid leukemia
  • apoptosis
  • cytarabine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism'. Together they form a unique fingerprint.

Cite this