Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Yael Cohen-Sharir, James M McFarland, Mai Abdusamad, Carolyn Marquis, Sara V Bernhard, Mariya Kazachkova, Helen Tang, Marica R Ippolito, Kathrin Laue, Johanna Zerbib, Heidi L H Malaby, Andrew Jones, Lisa-Marie Stautmeister, Irena Bockaj, René Wardenaar, Nicholas Lyons, Ankur Nagaraja, Adam J Bass, Diana C J Spierings, Floris FoijerRameen Beroukhim, Stefano Santaguida, Todd R Golub, Jason Stumpff, Zuzana Storchová, Uri Ben-David

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

Selective targeting of aneuploid cells is an attractive strategy for cancer treatment(1). However, it is unclear whether aneuploidy generates any clinically relevant vulnerabilities in cancer cells. Here we mapped the aneuploidy landscapes of about 1,000 human cancer cell lines, and analysed genetic and chemical perturbation screens(2-9) to identify cellular vulnerabilities associated with aneuploidy. We found that aneuploid cancer cells show increased sensitivity to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis(10). Unexpectedly, we also found that aneuploid cancer cells were less sensitive than diploid cells to short-term exposure to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly sensitive to inhibition of SAC over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing when the SAC was inhibited, resulting in the accumulation of mitotic defects, and in unstable and less-fit karyotypes. Therefore, although aneuploid cancer cells could overcome inhibition of SAC more readily than diploid cells, their long-term proliferation was jeopardized. We identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to depletion of KIF18A, and KIF18A overexpression restored their response to SAC inhibition. Our results identify a therapeutically relevant, synthetic lethal interaction between aneuploidy and the SAC.

Original languageEnglish
Number of pages29
JournalNature
Volume590
Issue number7846
Early online date27-Jan-2021
DOIs
Publication statusPublished - 18-Feb-2021

Keywords

  • SPINDLE-ASSEMBLY CHECKPOINT
  • DRUG-SENSITIVITY
  • LARGE-SCALE
  • INSTABILITY
  • KIF18A
  • TUMORIGENESIS
  • CONNECTIVITY
  • DEPENDENCIES
  • VIABILITY
  • DISCOVERY

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