Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation

The emergence of resistance to imatinib mediated by mutations in the BCR-ABL has become a major challenge in the treatment of chronic myeloid leukemia (CML). Alternative therapeutic strategies to override imatinib-resistant CML are urgently needed. In this study, we investigated the effect of AKI603...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2016-11, Vol.6 (1), p.35533-35533, Article 35533
Main Authors: Wang, Le-Xun, Wang, Jun-Dan, Chen, Jia-Jie, Long, Bing, Liu, Ling-Ling, Tu, Xi-Xiang, Luo, Yu, Hu, Yuan, Lin, Dong-Jun, Lu, Gui, Long, Zi-Jie, Liu, Quentin
Format: Article
Language:English
Subjects:
13/1
13/109
14/34
14/63
692/308/1426
692/4028/67/1059/2326
96/2
96/31
96/98
Aurora kinase
BCR-ABL protein
Cell cycle
Cell proliferation
Chronic myeloid leukemia
Drug resistance
Enzyme inhibitors
Fusion protein
Humanities and Social Sciences
Imatinib
Leukemia
multidisciplinary
Mutation
Myeloid leukemia
Polyploidy
Reactive oxygen species
Science
Senescence
Xenografts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The emergence of resistance to imatinib mediated by mutations in the BCR-ABL has become a major challenge in the treatment of chronic myeloid leukemia (CML). Alternative therapeutic strategies to override imatinib-resistant CML are urgently needed. In this study, we investigated the effect of AKI603, a novel small molecule inhibitor of Aurora kinase A (AurA) to overcome resistance mediated by BCR-ABL-T315I mutation. Our results showed that AKI603 exhibited strong anti-proliferative activity in leukemic cells. AKI603 inhibited cell proliferation and colony formation capacities in imatinib-resistant CML cells by inducing cell cycle arrest with polyploidy accumulation. Surprisingly, inhibition of AurA by AKI603 induced leukemia cell senescence in both BCR-ABL wild type and T315I mutation cells. Furthermore, the induction of senescence was associated with enhancing reactive oxygen species (ROS) level. Moreover, the anti-tumor effect of AKI603 was proved in the BALB/c nude mice KBM5-T315I xenograft model. Taken together, our data demonstrate that the small molecule AurA inhibitor AKI603 may be used to overcome drug resistance induced by BCR-ABL-T315I mutation in CML.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep35533