Targeting Aurora Kinases in Acute Lymphoblastic Leukemia

Abstract

Despite improved treatment outcome in acute lymphoblastic leukemia (ALL) drug resistance and disease recurrence remain major obstacles in ALL Thus there is an urgent need to identify new targets for therapy Several studies showed that Aurora kinases were potential therapeutic targets in some cancers This study was aimed to investigate whether Aurora kinases would be the therapeutic targets in ALL Aurora kinases were overexpressed in ALL cell lines and patient samples by Western blot real-time quantitative PCR and immunohistochemistry and their expression pattern was associated with clinical outcomes Pan-Aurora kinase inhibitors VE-465 and VX-680 exhibited different drug susceptibilities in nine ALL cell lines Drug susceptibility of ALL cells was not correlated with the expression status of Aurora kinases their phosphorylation or activators Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC50 around 10–40 nM and displayed a phenotype of Aurora-A inhibition whereas cells resistant to Aurora kinase inhibitors (with an IC50 more than 10 μM) accumulated polyploidy which resulted from Aurora-B inhibition Furthermore drug-sensitive MLL-AF4-positive cell lines and xenograft mice also had good anti-leukemia responses to specific Aurora-A inhibitors (MLN8237) but responded poorly to specific Aurora-B inhibitors (ZM447439) The further molecular mechanism demonstrated that CDKN1A played a critical role in governing the drug responsiveness of ALL in a TP53-independent manner Primary MLL-AF4-positve ALL cells exhibiting high CDKN1A expression were sensitive to pan-Aurora kinase inhibitors Therefore our study suggested CDKN1A might serve as a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL particularly in MLL-AF4-positive patients

Date of Award	2014 Aug 29
Original language	English
Supervisor	Tsai-Yun Chen (Supervisor)