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

Mol Oncol. 2014 Dec;8(8):1404-18. doi: 10.1016/j.molonc.2014.05.007. Epub 2014 Jun 2.

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.

Keywords: Drug screening; Drug-resistance; Eg5; Infrared; Kinesin; Mitosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / genetics
  • Aurora Kinase A / metabolism*
  • Benzamides / pharmacology
  • Chromones / pharmacology
  • Drug Resistance
  • Drug Synergism
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • Kinesin / genetics
  • Kinesin / metabolism*
  • Microscopy, Fluorescence
  • Mitosis / drug effects
  • RNA Interference

Substances

  • Benzamides
  • Chromones
  • KIF11 protein, human
  • KIF15 protein, human
  • SB 743921
  • Aurora Kinase A
  • Kinesin