Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition

Klaske M Schukken, Yu-Chih Lin, Petra L Bakker, Michael Schubert, Stephanie F Preuss, Judith E Simon, Hilda van den Bos, Zuzana Storchova, Maria Colomé-Tatché, Holger Bastians, Diana Cj Spierings, Floris Foijer*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

4 Citaten (Scopus)
69 Downloads (Pure)

Samenvatting

Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.

Originele taal-2English
Artikelnummere201900499
Aantal pagina's15
TijdschriftLife science alliance
Volume3
Nummer van het tijdschrift2
DOI's
StatusPublished - feb-2020

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