The SKA complex is a mitotic vulnerability of chromosomally unstable cancers

Schoot Uiterkamp, M.; Coolen, E. S.; de Lint, K.; Tarrab, A.; Vukusic, K.; Rockx, D.; Rooimans, M. A.; de Kleijn, T.; Harmsen, I. J.; Leite de Oliveira, R.; Foijer, F.; Medema, R. H.; Tolic, I. M.; Ben-David, U.; Wolthuis, R. M. F.; Vader, G.

doi:10.64898/2026.05.21.726809

bioRxiv · 10.64898/2026.05.21.726809

The SKA complex is a mitotic vulnerability of chromosomally unstable cancers

Schoot Uiterkamp, M.·Coolen, E. S.·de Lint, K.·Tarrab, A.·Vukusic, K.·Rockx, D.·Rooimans, M. A.·de Kleijn, T.·Harmsen, I. J.·Leite de Oliveira, R.·Foijer, F.·Medema, R. H.·Tolic, I. M.·Ben-David, U.·Wolthuis, R. M. F.·Vader, G.

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Abstract

Aneuploidy and chromosomal instability are common characteristics of cancer but remain underexploited therapeutically. Because chromosomally unstable cells exhibit altered mitotic control, they are selectively vulnerable to inhibition of the kinesin KIF18A. Here, we identify the spindle and kinetochore-associated (SKA) complex as a mitotic regulator that establishes a similar dependency. SKA loss is tolerated in cells with a defective mitotic checkpoint, but when mitosis is prolonged, it leads to mitotic errors and loss of viability. Genetic analysis reveals that SKA and KIF18A are epistatic, although they function through mechanistically distinct mitotic pathways. SKA depletion selectively impacts chromosomally unstable cancer cells and mirrors the effects of KIF18A inhibition. We thus identify a cellular vulnerability associated with prolonged mitosis in chromosomally unstable cancers.

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Schoot Uiterkamp, M., Coolen, E. S., de Lint, K., Tarrab, A., Vukusic, K., Rockx, D., Rooimans, M. A., de Kleijn, T., Harmsen, I. J., Leite de Oliveira, R., Foijer, F., Medema, R. H., Tolic, I. M., Ben-David, U., Wolthuis, R. M. F., Vader, G.. 2026-05-21. The SKA complex is a mitotic vulnerability of chromosomally unstable cancers. https://doi.org/10.64898/2026.05.21.726809

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