Evolution of Resistance to Aurora Kinase B Inhibitors in Leukaemia Cells

We developed and characterised an in vitro leukaemia model of resistance to the Aurora B inhibitor ZM447439

Timothy W. Failes; Gorjana Mitic; Heba Abdel-Halim; Sela T. Po'uha; Marjorie Liu; David E. Hibbs; Maria Kavallaris


Scholarcy highlights

  • Mitotic kinases play crucial roles in regulation of cell division, yet aberrations in their expression and function are known to be involved in cancer initiation and progression
  • The CEM/AKB4 cells were hypersensitive to the Aurora A inhibitor MLN8237
  • Understanding the molecular factors that contribute to sensitivity and resistance to new chemotherapeutic agents is crucial to their effective implementation in treatment regimes
  • Characterisation of CEM/AKB4 cells revealed that resistance is not mediated by multidrug resistance pathways
  • Detection of a G160E point mutation in the kinase domain of Aurora B suggested that resistance in CEM/ AKB4 cells is mediated through impaired binding of the drug to the target kinase
  • Our findings in a leukaemia cell line further validate that the 160 position is important for drug binding and that point mutations of this residue afford highly penetrant resistance. This mutation should be validated in a clinical setting as it may be important in the use of Aurora B inhibitors and resistance to therapy, much as the T315I BCR-ABL mutation is highly prognostic of outcome for Imatinib treatment in CML patients
  • Our study of phosphorylated Histone H3 levels showed that CEM/AKB4 cells maintain resistance to Aurora B inhibition at 16 mM ZM, despite this drug concentration being sufficient to induce apoptosis and cell death

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