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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
113 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere201900499
Number of pages15
JournalLife science alliance
Volume3
Issue number2
DOIs
Publication statusPublished - Feb-2020

Keywords

  • CHROMOSOME SEGREGATION ERRORS
  • DNA-DAMAGE RESPONSE
  • MIS-SEGREGATION
  • COLORECTAL-CANCER
  • C-SRC
  • ANEUPLOIDY
  • INSTABILITY
  • CELLS
  • MPS1
  • CONSEQUENCES

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