The SKA complex is a mitotic vulnerability of chromosomally unstable cancers

Maud Schoot Uiterkamp; Elsa S. Coolen; Klaas de Lint; Adi V Tarrab; Kruno Vukušić; Davy Rockx; Martin A. Rooimans; Tess de Kleijn; Iris J. Harmsen; Rodrigo Leite de Oliveira; Floris Foijer; René H. Medema; Iva M. Tolić; Uri Ben‐David; Rob M.F. Wolthuis; Gerben Vader

doi:10.64898/2026.05.21.726809

Cell BiologybioRxivMay 21, 2026

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The SKA complex is a mitotic vulnerability of chromosomally unstable cancers

Maud Schoot Uiterkamp iD, Elsa S. Coolen, Klaas de Lint iD, Adi V Tarrab, Kruno Vukušić iD, Davy Rockx, Martin A. Rooimans iD, Tess de Kleijn, Iris J. Harmsen iD, Rodrigo Leite de Oliveira iD, Floris Foijer iD, René H. Medema iD, Iva M. Tolić iD, Uri Ben‐David iD, Rob M.F. Wolthuis iD, Gerben Vader iD

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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.