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Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Author

Listed:
  • 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
    Dana Farber Cancer Institute)

  • Adam J. Bass

    (Cancer Program, Broad Institute of MIT and Harvard
    Dana Farber Cancer Institute)

  • Diana C. J. Spierings

    (University of Groningen)

  • Floris Foijer

    (University of Groningen)

  • Rameen Beroukhim

    (Cancer Program, Broad Institute of MIT and Harvard
    Dana Farber Cancer Institute)

  • Stefano Santaguida

    (European Institute of Oncology IRCCS
    University of Milan)

  • Todd R. Golub

    (Cancer Program, Broad Institute of MIT and Harvard
    Dana Farber Cancer Institute)

  • Jason Stumpff

    (University of Vermont)

  • Zuzana Storchová

    (TU Kaiserlautern)

  • Uri Ben-David

    (Faculty of Medicine)

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.

Suggested Citation

  • 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 &, 2021. "Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition," Nature, Nature, vol. 590(7846), pages 486-491, February.
  • Handle: RePEc:nat:nature:v:590:y:2021:i:7846:d:10.1038_s41586-020-03114-6
    DOI: 10.1038/s41586-020-03114-6
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    Citations

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    Cited by:

    1. Lorenza Garribba & Giuseppina De Feudis & Valentino Martis & Martina Galli & Marie Dumont & Yonatan Eliezer & René Wardenaar & Marica Rosaria Ippolito & Divya Ramalingam Iyer & Andréa E. Tijhuis & Dia, 2023. "Short-term molecular consequences of chromosome mis-segregation for genome stability," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Joana S. Rodrigues & Miguel Chenlo & Susana B. Bravo & Sihara Perez-Romero & Maria Suarez-Fariña & Tomas Sobrino & Rebeca Sanz-Pamplona & Román González-Prieto & Manuel Narciso Blanco Freire & Ruben N, 2024. "dsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe," Nature Communications, Nature, vol. 15(1), pages 1-30, December.
    3. Shixiang Wang & Chen-Yi Wu & Ming-Ming He & Jia-Xin Yong & Yan-Xing Chen & Li-Mei Qian & Jin-Ling Zhang & Zhao-Lei Zeng & Rui-Hua Xu & Feng Wang & Qi Zhao, 2024. "Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Leanne M. Brown & Ryan A. Hagenson & Tilen Koklič & Iztok Urbančič & Lu Qiao & Janez Strancar & Jason M. Sheltzer, 2024. "An elevated rate of whole-genome duplications in cancers from Black patients," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. Johanna Zerbib & Marica Rosaria Ippolito & Yonatan Eliezer & Giuseppina Feudis & Eli Reuveni & Anouk Savir Kadmon & Sara Martin & Sonia Viganò & Gil Leor & James Berstler & Julia Muenzner & Michael Mü, 2024. "Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Akshaya Ramakrishnan & Aikaterini Symeonidi & Patrick Hanel & Katharina T. Schmid & Maria L. Richter & Michael Schubert & Maria Colomé-Tatché, 2023. "epiAneufinder identifies copy number alterations from single-cell ATAC-seq data," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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