Cancer cells with abnormal chromosome numbers were sensitive to spindle assembly checkpoint inhibition.
Major Finding: Cancer cells with abnormal chromosome numbers were sensitive to spindle assembly checkpoint inhibition.
Concept: KIF18A, encoding a kinesin superfamily molecular motor, was a key dependency in these cells.
Impact: This work identifies a target in cells that exhibit aneuploidy, which is a common feature of cancer.
Abnormal chromosome number, including both aneuploidy and whole-genome doubling (WGD), is a common feature of cancer cells that is normally absent in nonmalignant cells, but whether these genetic aberrations are therapeutically targetable has not been established. Complementary work by Quinton and colleagues along with Cohen-Sharir and colleagues revealed that the spindle assembly checkpoint was a vulnerability of cancer cells with an abnormal number of chromosomes. To approach the question, Quinton and colleagues analyzed sequencing data from approximately 10,000 primary human cancer samples and genetic essentiality data from about 600 cell lines, whereas Cohen-Sharir and colleagues investigated aneuploidy in roughly 1,000 human cancer cell lines, leveraging genetic and chemical perturbation screens to pinpoint vulnerabilities. Counterintuitively, Cohen-Sharir and colleagues found that aneuploid cancer cells were less susceptible than diploid cells to brief pharmacologic inhibition of the spindle assembly checkpoint using a variety of inhibitors; rather than halting cell division upon this inhibition, the aneuploid cells adopted alternate spindle geometry and dynamics. This caused mitotic defects, exacerbating the already abnormal karyotypes of the aneuploid cancer cells and leading to increased sensitivity to inhibition of the spindle assembly checkpoint over time. Additionally, both groups pinpointed KIF18A, encoding a microtubule-associated molecular motor in the kinesin superfamily that is involved in the spindle assembly checkpoint, as a key dependency of aneuploid cancer cells. Specifically, Quinton and colleagues determined that KIF18A loss was tolerated by diploid cells but led to mitotic defects and reduced viability in cells that had undergone WGD. Further, Cohen-Sharir and colleagues found that KIF18A overexpression sensitized aneuploid cancer cells to inhibition of the spindle assembly checkpoint. Together, the work of these two groups establishes the spindle assembly checkpoint and KIF18A as specific vulnerabilities of cancer cells with chromosome copy-number aberrations, providing insight into a process that may be targetable.
Cohen-Sharir Y, McFarland JM, Abdusamad M, Marquis C, Bernhard SV, Kazachkova M, et al. Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature 2021 Jan 27 [Epub ahead of print].
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