Abstract
Aurora kinase inhibitors are new mitosis-targeting drugs currently in clinical trials for the treatment of haematological and solid malignancies. However, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Herein, we developed and characterised an in vitro leukaemia model of resistance to the Aurora B inhibitor ZM447439. Human T-cell acute lymphoblastic leukaemia cells, CCRF-CEM, were selected for resistance in 4 µM ZM447439. CEM/AKB4 cells showed no cross-resistance to tubulin-targeted and DNA-damaging agents, but were hypersensitive to an Aurora kinase A inhibitor. Sequencing revealed a mutation in the Aurora B kinase domain corresponding to a G160E amino acid substitution. Molecular modelling of drug binding in Aurora B containing this mutation suggested that resistance is mediated by the glutamate substitution preventing formation of an active drug-binding motif. Progression of resistance in the more highly selected CEM/AKB8 and CEM/AKB16 cells, derived sequentially from CEM/AKB4 in 8 and 16 µM ZM447439 respectively, was mediated by additional defects. These defects were independent of Aurora B and multi-drug resistance pathways and are associated with reduced apoptosis mostly likely due to reduced inhibition of the catalytic activity of aurora kinase B in the presence of drug. Our findings are important in the context of the use of these new targeted agents in treatment regimes against leukaemia and suggest resistance to therapy may arise through multiple independent mechanisms.
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
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
Summary
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. Targeting these kinases has proven in recent years to be an exciting avenue for alternative cancer therapies [1]. Increased expression of Aurora A has been reported in many leukaemias, while the expression of Aurora B has shown no clear trend [11,12,13] Both Aurora A and B have been exploited as potential targets for therapeutic intervention
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