Tetraploidy‐linked sensitization to CENP‐E inhibition in human cells

Abstract

Tetraploidy is a hallmark of cancer cells, and tetraploidy‐selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti‐proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin (CENP‐E) than are diploids. Treatment with a CENP‐E inhibitor preferentially diminished the tetraploid cell population in a diploid–tetraploid co‐culture at optimum conditions. Live imaging revealed that a tetraploidy‐linked increase in unsolvable chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP‐E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy‐selective cell growth suppression. In contrast, the microtubule‐stabilizing compound paclitaxel caused tetraploidy‐selective suppression through the aggravation of spindle multipolarization. We also found that treatment with a CENP‐E inhibitor had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP‐E inhibitors in tetraploidy‐selective suppression and their potential use in the development of tetraploidy‐targeting interventions in cancer.

CENP-E initiates chromosome congression by opposing Aurora kinases to promote end-on attachments

“…We speculate that these differences arise due to divergent time-dependent changes of microtubule stability 78,97 after mitotic prolongation between chromosomally unstable cancer cells and non-transformed cells, which could preclude initiation of congression in the absence of CENP-E specifically in these cancers. Interestingly, since it was recently shown that tetraploid cells are significantly more susceptible to CENP-E inhibitors 98 and to perturbation of the Kif18a motor 99 compared to their diploid counterparts, we hypothesize that these observations could be part of a common theme of divergent responses of chromosomally stable and unstable cells to mitotic prolongation. We envisage that these divergent responses are the result of faulty chromosome congression and SAC activation in chromosomally unstable cells, which could be a valuable path to explore in the development of new tumor treatment strategies specifically targeting aneuploid cells.…”

“…We propose that the duration of mitosis influences the stability of kinetochore microtubules (Bakhoum et al, 2009;Kabeche & Compton, 2013) in a manner that impedes congression initiation specifically in CENP-E-deficient cancer cells compared to non-transformed cells during prolonged mitosis. Recent studies have shown that tetraploid cells are more vulnerable to CENP-E inhibitors (Yoshizawa et al, 2023) and Kif18a inhibitors (Quinton et al, 2021) than diploid cells, likely due to their prolonged mitotic duration (Gliech et al, 2024). We hypothesize that these differential effects of kinesin inhibitors stem from distinct responses to mitotic prolongation between chromosomally stable and unstable cells.…”

Kinetochore and ionomic adaptation to whole genome duplication

“…An essential kinetochore protein, CENP-E moves mono-oriented chromosomes to the spindle equator, mediating congression 51,71,72 . Strikingly, tetraploid cancers are far more susceptible to CENP-E inhibitors than diploids 52–54,73,74 .…”

“…Strikingly, tetraploid cancers are far more susceptible to CENP-E inhibitors than diploids [52][53][54]73,74 .…”

Kinesin-7 CENP-E in tumorigenesis: Chromosome instability, spindle assembly checkpoint, and applications

“…The combination of GSK923295 and pharmacologic inhibitors of mitogen-activated ERK kinase (MEK1/2) shows a significant synergistic growth inhibition on neuroblastoma, lung, pancreatic, and colon carcinoma cell lines, which further results in mitotic arrest and apoptosis (Mayes et al, 2013). GSK923295 significantly inhibits the proliferation of tetraploid cells compared with diploids, suggesting superior generality of CENP-E-targeted tetraploidy inhibition (Yoshizawa et al, 2023). These findings indicate that in cancer treatment, exploring the combination of GSK923295 with other antitumor drugs might improve its clinical application.…”