A novel small molecule aurora kinase inhibitor attenuates breast tumor-initiating cells and overcomes drug resistance

  • Mol Cancer Ther. 2014 Aug;13(8):1991-2003. doi: 10.1158/1535-7163.MCT-13-1029.
Fei-Meng Zheng  1 ,  Zi-Jie Long  2 ,  Zhi-Jie Hou  3 ,  Yu Luo  4 ,  Ling-Zhi Xu  3 ,  Jiang-Long Xia  3 ,  Xiao-Ju Lai  5 ,  Ji-Wei Liu  3 ,  Xi Wang  5 ,  Muhammad Kamran  3 ,  Min Yan  5 ,  Shu-Juan Shao  6 ,  Eric W-F Lam  7 ,  Shao-Wu Wang  3 ,  Gui Lu  8 ,  Quentin Liu  9
Affiliations
  • 1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine; Institute of Cancer Stem Cell, Dalian Medical University; Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
  • 2. Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University;
  • 3. Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
  • 4. Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou;
  • 5. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine; Institute of Cancer Stem Cell, Dalian Medical University;
  • 6. Department of Histology and Embryology, Dalian Medical University, Dalian, China; and.
  • 7. Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College London, London, United Kingdom.
  • 8. Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou; [email protected] [email protected] [email protected].
  • 9. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine; Institute of Cancer Stem Cell, Dalian Medical University; Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University; Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology; [email protected] [email protected] [email protected].
PMID: 24899685 DOI: 10.1158/1535-7163.MCT-13-1029
Abstract

Chemoresistance is a major cause of Cancer treatment failure. Tumor-initiating cells (TIC) have attracted a considerable amount of attention due to their role in chemoresistance and tumor recurrence. Here, we evaluated the small molecule Aurora Kinase Inhibitor AKI603 as a novel agent against TICs in breast Cancer. AKI603 significantly inhibited Aurora-A (AurA) kinase and induced cell-cycle arrest. In addition, the intragastric administration of AKI603 reduced xenograft tumor growth. Interestingly, we found that breast Cancer cells that were resistant to epirubicin expressed a high level of activated AurA and also have a high CD24(Low)/CD44(High) TIC population. The inhibition of AurA kinase by AKI603 abolished the epirubicin-induced enrichment of TICs. Moreover, AKI603 suppressed the capacity of cells to form mammosphere and also suppressed the expression of self-renewal genes (β-catenin, c-Myc, Sox2, and Oct4). Thus, our work suggests the potential clinical use of the small molecule Aurora Kinase Inhibitor AKI603 to overcome drug resistance induced by conventional chemotherapeutics in breast Cancer.

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