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Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition
Yael Cohen-Sharir1, James M McFarland2, Mai Abdusamad2
1Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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.
Insights
Aneuploid cancer cells exhibit unique vulnerabilities. Targeting the spindle assembly checkpoint (SAC) reveals long-term proliferation defects and identifies KIF18A as a potential therapeutic target for cancer treatment.
Area of Science:
- Cancer biology
- Cellular and molecular oncology
- Genetics
Background:
- Aneuploidy, an abnormal chromosome number, is common in cancer but its therapeutic implications are not fully understood.
- Selective targeting of aneuploid cells offers a promising cancer treatment strategy.
- Identifying clinically relevant vulnerabilities in aneuploid cancer cells is crucial.
Purpose of the Study:
- To map aneuploidy landscapes in human cancer cell lines.
- To identify cellular vulnerabilities associated with aneuploidy using genetic and chemical screens.
- To investigate the therapeutic potential of targeting aneuploidy.
Main Methods:
- Analysis of aneuploidy landscapes across ~1,000 human cancer cell lines.
- Evaluation of genetic and chemical perturbation screens.
- Assessment of cancer cell sensitivity to spindle assembly checkpoint (SAC) inhibitors.
- Investigation of KIF18A's role in aneuploid cells.
Main Results:
- Aneuploid cancer cells show increased sensitivity to genetic perturbation of SAC components.
- Aneuploid cells exhibit delayed sensitivity to short-term SAC inhibition, leading to mitotic defects and karyotype instability.
- KIF18A depletion selectively harms aneuploid cells, while its overexpression rescues SAC inhibition sensitivity.
- A synthetic lethal interaction between aneuploidy and SAC inhibition was identified.
Conclusions:
- Aneuploid cancer cells possess long-term proliferation defects when the SAC is inhibited.
- KIF18A is a key factor in aneuploid cell response to SAC inhibition.
- The identified synthetic lethality between aneuploidy and SAC inhibition presents a potential therapeutic avenue for cancer treatment.
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