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, 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.
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.|Department of Cardiac Surgery II, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2 Road, Guangzhou 510080, China.
Le-Xun
LX
Wang
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.
Jun-Dan
JD
Wang
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.
Jia-Jie
JJ
Chen
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.
Bing
B
Long
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.
Ling-Ling
LL
Liu
Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
Xi-Xiang
XX
Tu
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Road East, Guangzhou 510006, China.
Yu
Y
Luo
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.
Yuan
Y
Hu
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.
Dong-Jun
DJ
Lin
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Road East, Guangzhou 510006, China.
Gui
G
Lu
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.
Zi-Jie
ZJ
Long
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.|Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.|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.
Quentin
Q
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C000597114:AKI603; D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl