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Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

Yael Cohen-Sharir, James M. McFarland, Mai Abdusamad, Carolyn Marquis, Helen Tang, Marica R. Ippolito, Sara V. Bernhard, Kathrin Laue, Heidi L.H. Malaby, Andrew Jones, Mariya Kazachkova, Nicholas Lyons, Ankur Nagaraja, Adam J. Bass, Rameen Beroukhim, Stefano Santaguida, Jason Stumpff, Todd R. Golub, Zuzana Storchova, View ORCID ProfileUri Ben-David
doi: https://doi.org/10.1101/2020.06.18.159038
Yael Cohen-Sharir
1Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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James M. McFarland
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Mai Abdusamad
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Carolyn Marquis
3Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT, USA
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Helen Tang
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Marica R. Ippolito
4Department of Experimental Oncology at IEO, European Institute of Oncology IRCCS, Milan, Italy
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Sara V. Bernhard
5Department of Molecular Genetics, TU Kaiserlautern, Kaiserlautern, Germany
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Kathrin Laue
1Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Heidi L.H. Malaby
3Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT, USA
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Andrew Jones
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Mariya Kazachkova
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Nicholas Lyons
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Ankur Nagaraja
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Dana Farber Cancer Institute, Boston, MA, USA
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Adam J. Bass
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Dana Farber Cancer Institute, Boston, MA, USA
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Rameen Beroukhim
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Dana Farber Cancer Institute, Boston, MA, USA
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Stefano Santaguida
4Department of Experimental Oncology at IEO, European Institute of Oncology IRCCS, Milan, Italy
7Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Jason Stumpff
3Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT, USA
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Todd R. Golub
2Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Department of Experimental Oncology at IEO, European Institute of Oncology IRCCS, Milan, Italy
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Zuzana Storchova
5Department of Molecular Genetics, TU Kaiserlautern, Kaiserlautern, Germany
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Uri Ben-David
1Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • ORCID record for Uri Ben-David
  • For correspondence: ubendavid@tauex.tau.ac.il
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Abstract

Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines and classified them by their degree of aneuploidy. Next, we performed a comprehensive analysis of large-scale genetic and chemical perturbation screens, in order to compare the cellular vulnerabilities between near-diploid and highly-aneuploid cancer cells. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found highly-aneuploid cancer cells to be less sensitive to short-term exposures to multiple inhibitors of the SAC regulator TTK. To resolve this paradox and to uncover its mechanistic basis, we established isogenic systems of near-diploid cells and their aneuploid derivatives. Using both genetic and chemical inhibition of BUB1B, MAD2 and TTK, we found that the cellular response to SAC inhibition depended on the duration of the assay, as aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. The increased ability of aneuploid cells to slip from mitotic arrest and to keep dividing in the presence of SAC inhibition was coupled to aberrant spindle geometry and dynamics. This resulted in a higher prevalence of mitotic defects, such as multipolar spindles, micronuclei formation and failed cytokinesis. Therefore, although aneuploid cancer cells can overcome SAC inhibition more readily than diploid cells, the proliferation of the resultant aberrant cells is jeopardized. At the molecular level, analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose levels were drastically reduced in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored the sensitivity of aneuploid cancer cells to SAC inhibition. In summary, we identified an increased vulnerability of aneuploid cancer cells to SAC inhibition and explored its cellular and molecular underpinnings. Our results reveal a novel synthetic lethal interaction between aneuploidy and the SAC, which may have direct therapeutic relevance for the clinical application of SAC inhibitors.

Competing Interest Statement

T.R.G. is a consultant to GlaxoSmithKline and is a founder of Sherlock Biosciences. R.B. own shares in Ampressa and receives grant funding from Novartis. A.J.B. receives funding from Merck, Bayer and Novartis, and is an advisor to Earli and Helix Nano and a co-founder of Signet Therapeutics. The other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 19, 2020.
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Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint
Yael Cohen-Sharir, James M. McFarland, Mai Abdusamad, Carolyn Marquis, Helen Tang, Marica R. Ippolito, Sara V. Bernhard, Kathrin Laue, Heidi L.H. Malaby, Andrew Jones, Mariya Kazachkova, Nicholas Lyons, Ankur Nagaraja, Adam J. Bass, Rameen Beroukhim, Stefano Santaguida, Jason Stumpff, Todd R. Golub, Zuzana Storchova, Uri Ben-David
bioRxiv 2020.06.18.159038; doi: https://doi.org/10.1101/2020.06.18.159038
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Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint
Yael Cohen-Sharir, James M. McFarland, Mai Abdusamad, Carolyn Marquis, Helen Tang, Marica R. Ippolito, Sara V. Bernhard, Kathrin Laue, Heidi L.H. Malaby, Andrew Jones, Mariya Kazachkova, Nicholas Lyons, Ankur Nagaraja, Adam J. Bass, Rameen Beroukhim, Stefano Santaguida, Jason Stumpff, Todd R. Golub, Zuzana Storchova, Uri Ben-David
bioRxiv 2020.06.18.159038; doi: https://doi.org/10.1101/2020.06.18.159038

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