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

Abstract

Eg5 Infrared Kinesin Mitosis A B S T R A C TThe 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, drugresistance 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.

Kinesin-5 inhibitor resistance is driven by kinesin-12

“…Kif15 is critical for mitotic progression in KIRC-1-3 and also in a limited number of KIRCs analyzed in previous studies (Raaijmakers et al, 2012;Sturgill and Ohi, 2013;Ma et al, 2014). The extent to which Kif15 drives the acquisition of K5I resistance within a cell population, however, has not been systematically tested.…”

“…Eg5 also contains unique structural features that dispose the motor to small-molecule inhibitors (Brier et al, 2004;Cox et al, 2005;Maliga and Mitchison, 2006;Lad et al, 2008). We and others have capitalized on Eg5 inhibitors (K5Is) to reveal auxiliary spindle assembly pathways that emerge after chronic exposure K5Is (Raaijmakers et al, 2012;Sturgill and Ohi, 2013;Ma et al, 2014). This approach has improved our understanding of spindle physiology and adaptability, revealing that cytoplasmic dynein and the kinesin-12 Kif15 can drive centrosome separation in K5I-resistant cells (Raaijmakers et al, 2012;Sturgill and Ohi, 2013).…”

Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

“…Together with cell biological evidence that inhibition of AurA compromises mitotic progression, an increased AurA expression profile in cancer supports that AurA is a clinically relevant drug target (48). Pharmaceutical companies have begun to exploit this possibility, bringing numerous targeted inhibitors to the market as anti-cancer drugs, and spurring clinical trials (37,(49)(50)(51)(52)(53)(54)(55). However, while the efficacy and safety of inhibiting AurA have been supported by preclinical and early stage clinical trials, response to AurA inhibition has been limited (37, 55-57) and it remains unclear which patients may best benefit from AurA inhibitor treatment either alone, or in combination with standard chemotherapeutic approaches.…”

K-fiber bundles in the mitotic spindle are mechanically reinforced by Kif15

“…This redundancy between Kif15 and Eg5 is of interest as a potential factor in the disappointing ineffectiveness thus far of Eg5 inhibitors as cancer therapeutics (Tanenbaum et al , 2009;Rath and Kozielski, 2012;Milic et al , 2018;Dumas et al , 2019) . It is particularly notable since Kif15 overexpression results in lagging chromosomes (Malaby et al , 2019) , and is upregulated in a number of cancers (Ma et al , 2014;Wang et al , 2017;Qiao et al , 2018;Yu et al , 2019;Zhao et al , 2019;Sun et al , 2020;Terribas et al , 2020) . Under normal circumstances, however, Kif15 localizes predominantly to k-fiber microtubules.…”

“…This redundancy between Kif15 and Eg5 is of particular interest as a potential factor in the disappointing ineffectiveness thus far of Eg5 inhibitors as cancer therapeutics (Tanenbaum et al 2009;Milic et al 2018;Dumas et al 2019;Rath and Kozielski 2012) . Furthermore, Kif15 upregulation is found in a number of cancer types and can result in rapid cancer cell proliferation (Wang et al 2017;Zhao et al 2019;Yu et al 2019;Qiao et al 2018;Sun et al 2020;Terribas et al 2020;Ma et al 2014) . Under normal circumstances, however, Kif15 localizes predominantly to k-fiber microtubules.…”