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

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

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.

Figures
Products