Aneuploidy-induced sensitivity to spindle assembly checkpoint inhibition

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. A comprehensive analysis of large-scale genetic and chemical perturbation screens revealed differential cellular vulnerabilities between near-euploid 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. Indeed, aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing in the presence of SAC inhibition, resulting in a higher prevalence of mitotic defects. Single-cell DNA sequencing revealed that aneuploid cells acquired more chromosomal aberrations following SAC inhibition, leading to unstable and less fit karyotypes. Therefore, although aneuploid cancer cells could overcome SAC inhibition more readily than diploid cells, the long-term proliferation of the resultant aberrant cells was jeopardized. Analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored their sensitivity to SAC inhibition. 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.