title: Synergism between inhibitors of Aurora A and KIF11 overcomes KIF15-dependent drug resistance.
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.
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Hoi Tang
authors.initials: HT
authors.lastname: Ma
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Sergio
authors.initials: S
authors.lastname: Erdal
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. Electronic address: rycpoon@ust.hk.
authors.forename: Randy Y C
authors.initials: RY
authors.lastname: Poon
mesh_terms: D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects; D034622:RNA Interference
chemical_list: D001549:Benzamides; D002867:Chromones; C470243:KIF11 protein, human; C486567:KIF15 protein, human; C557279:SB 743921; D064096:Aurora Kinase A; D016547:Kinesins
keywords: Drug screening; Drug-resistance; Eg5; Infrared; Kinesin; Mitosis