title: A novel small molecule aurora kinase inhibitor attenuates breast tumor-initiating cells and overcomes drug resistance.
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.
authors.affiliation: 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;
authors.forename: Fei-Meng
authors.initials: FM
authors.lastname: Zheng
authors.affiliation: Department of Hematology, Third Affiliated Hospital, Sun Yat-sen University;
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.affiliation: Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Hou
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou;
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Xu
authors.affiliation: Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
authors.forename: Jiang-Long
authors.initials: JL
authors.lastname: Xia
authors.affiliation: 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;
authors.forename: Xiao-Ju
authors.initials: XJ
authors.lastname: Lai
authors.affiliation: Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Liu
authors.affiliation: 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;
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
authors.forename: Muhammad
authors.initials: M
authors.lastname: Kamran
authors.affiliation: 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;
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Histology and Embryology, Dalian Medical University, Dalian, China; and.
authors.forename: Shu-Juan
authors.initials: SJ
authors.lastname: Shao
authors.affiliation: Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College London, London, United Kingdom.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Institute of Cancer Stem Cell, Institute of Cancer Stem Cell - First Affiliated Hospital Collaborative Innovation Center of Oncology;
authors.forename: Shao-Wu
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou; liuq9@mail.sysu.edu.cn liuqiang@dlmedu.edu.cn lugui@mail.sysu.edu.cn.
authors.forename: Gui
authors.initials: G
authors.lastname: Lu
authors.affiliation: 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; liuq9@mail.sysu.edu.cn liuqiang@dlmedu.edu.cn lugui@mail.sysu.edu.cn.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000597114:AKI603; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D015251:Epirubicin; C576917:AURKA protein, human; D064096:Aurora Kinase A