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

Le-Xun Wang,Dong-Jun Lin,Zi-Jie Long,Xi-Xiang Tu,Jun-Dan Wang,Quentin Liu,Yuan Hu,Jia-Jie Chen,Yu Luo,Ling-Ling Liu,Gui Lu,Bing Long

doi:10.1038/srep35533

Abstract

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.

Highlights

The discovery that Aurora kinase A (AurA) was abnormally expressed in malignancies including leukemia prompted the development of agents that inhibited kinase activity[12]
We recently reported that AKI603 could inhibit the proliferation of breast cancer cells[21]
To evaluate the effect of AKI603 on proliferation of leukemic cells, six leukemic cell lines (AML: U937, HL-60 and NB4; chronic myeloid leukemia (CML): KBM5 and K562; ALL: Jurkat) were treated with various concentrations of AKI603 for 48 h, and the cell proliferation was determined by cell counting assay and CFSE staining assay

Summary

Introduction

The discovery that AurA was abnormally expressed in malignancies including leukemia prompted the development of agents that inhibited kinase activity[12]. Leukemia cells expressing T315I mutant form of BCR-ABL in vitro, in vivo and in patients[18,19,20]. Those studies indicate that AurA inhibitors exhibit a desirable therapeutic index in resistance of CML to imatinib caused by the T315I mutation. The aim of this study was to investigate the antineoplastic effects of the novel AurA small molecule inhibitor AKI603 in CML cells. AKI603 inhibited cell proliferation and induced senescence both in BCR-ABL wild-type and BCR-ABL-T315I mutant CML cells as well as in nude mouse xenograft models. The results revealed that AKI603 could efficiently overcome imatinib resistance of CML in vitro and in vivo

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Conclusion