Evolution of resistance to Aurora kinase B inhibitors in leukaemia cells.

PloS One
Timothy W FailesMaria Kavallaris

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 like...Continue Reading

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Citations

Nov 14, 2014·Open Biology·Florence H GohardWilliam C Earnshaw
Oct 29, 2013·Leukemia & Lymphoma·Vanessa S SilveiraCarlos Alberto Scrideli
Jan 3, 2014·International Journal of Cancer. Journal International Du Cancer·Ya-Ping ChenTsai-Yun Chen
Dec 17, 2016·Interdisciplinary Sciences, Computational Life Sciences·Rajashekar VadlakondaSreenivas Enaganti
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Naheed Arfin Borah, Mamatha M Reddy

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Methods Mentioned

BETA
flow cytometry
PCR

Software Mentioned

MacroModel
Pro Plus
GraphPad Prism
Maestro
Image
CellQuest

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