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 Foijer, Rameen Beroukhim, Stefano Santaguida, Todd R. Golub, Jason Stumpff, Zuzana Storchová and Uri Ben-David ()
Additional contact information
Yael Cohen-Sharir: Faculty of Medicine
James M. McFarland: Cancer Program, Broad Institute of MIT and Harvard
Mai Abdusamad: Cancer Program, Broad Institute of MIT and Harvard
Carolyn Marquis: University of Vermont
Sara V. Bernhard: TU Kaiserlautern
Mariya Kazachkova: Cancer Program, Broad Institute of MIT and Harvard
Helen Tang: Cancer Program, Broad Institute of MIT and Harvard
Marica R. Ippolito: European Institute of Oncology IRCCS
Kathrin Laue: Faculty of Medicine
Johanna Zerbib: Faculty of Medicine
Heidi L. H. Malaby: University of Vermont
Andrew Jones: Cancer Program, Broad Institute of MIT and Harvard
Lisa-Marie Stautmeister: TU Kaiserlautern
Irena Bockaj: University of Groningen
René Wardenaar: University of Groningen
Nicholas Lyons: Cancer Program, Broad Institute of MIT and Harvard
Ankur Nagaraja: Cancer Program, Broad Institute of MIT and Harvard
Adam J. Bass: Cancer Program, Broad Institute of MIT and Harvard
Diana C. J. Spierings: University of Groningen
Floris Foijer: University of Groningen
Rameen Beroukhim: Cancer Program, Broad Institute of MIT and Harvard
Stefano Santaguida: European Institute of Oncology IRCCS
Todd R. Golub: Cancer Program, Broad Institute of MIT and Harvard
Jason Stumpff: University of Vermont
Zuzana Storchová: TU Kaiserlautern
Uri Ben-David: Faculty of Medicine

Nature, 2021, vol. 590, issue 7846, 486-491

Abstract: Abstract Selective targeting of aneuploid cells is an attractive strategy for cancer treatment1. 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 screens2–9 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 mitosis10. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03114-6

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