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

  • Sci Rep. 2016 Nov 8;6:35533. doi: 10.1038/srep35533.
Le-Xun Wang  1  2 ,  Jun-Dan Wang  1 ,  Jia-Jie Chen  1 ,  Bing Long  1 ,  Ling-Ling Liu  1 ,  Xi-Xiang Tu  3 ,  Yu Luo  4 ,  Yuan Hu  1 ,  Dong-Jun Lin  1 ,  Gui Lu  4 ,  Zi-Jie Long  1 ,  Quentin Liu  1  3  5
Affiliations
  • 1. Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou 510630, China; Institute of Hematology, Sun Yat-sen University, Guangzhou 510630, China.
  • 2. Department of Cardiac Surgery II, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2 Road, Guangzhou 510080, China.
  • 3. Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
  • 4. Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Road East, Guangzhou 510006, China.
  • 5. Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng East Road, Guangzhou 510060, China.
PMID: 27824120 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.

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