Synergism between inhibitors of Aurora A and KIF11 overcomes KIF15-dependent drug resistance

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Abstract

The mitotic kinesin KIF11 (also called Eg5) plays critical roles in spindle functions. Although a number of small-molecule inhibitors of KIF11 are currently in clinical development, drug-resistance could be developed through compensation by another kinesin called KIF15. Using a newly developed infrared-based cell system, we discovered that the effectiveness of one of the latest generations of KIF11 inhibitor (SB743921) could be enhanced with several inhibitors of Aurora A kinase. Evidence including live-cell imaging and isobologram analysis indicated that targeting KIF11 and Aurora A together promoted monoastral spindle formation and mitotic catastrophe synergistically, supporting a model of parallel pathways of centrosome regulation by Aurora A and KIF11. We also developed a KIF15-dependent SB743921-resistance cell model. Significantly, the drug-resistance could also be overcome with Aurora A inhibitors. These results provide a molecular basis for increasing the effectiveness of Aurora A and KIF11 inhibitors and tackling problems of drug resistance.

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Ma, H. T., Erdal, S., Huang, S., & Poon, R. Y. C. (2014). Synergism between inhibitors of Aurora A and KIF11 overcomes KIF15-dependent drug resistance. Molecular Oncology, 8(8), 1404–1418. https://doi.org/10.1016/j.molonc.2014.05.007

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