RT Journal Article
SR Electronic
T1 Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.18.159038
DO 10.1101/2020.06.18.159038
A1 Yael Cohen-Sharir
A1 James M. McFarland
A1 Mai Abdusamad
A1 Carolyn Marquis
A1 Helen Tang
A1 Marica R. Ippolito
A1 Sara V. Bernhard
A1 Kathrin Laue
A1 Heidi L.H. Malaby
A1 Andrew Jones
A1 Mariya Kazachkova
A1 Nicholas Lyons
A1 Ankur Nagaraja
A1 Adam J. Bass
A1 Rameen Beroukhim
A1 Stefano Santaguida
A1 Jason Stumpff
A1 Todd R. Golub
A1 Zuzana Storchova
A1 Uri Ben-David
YR 2020
UL http://biorxiv.org/content/early/2020/06/19/2020.06.18.159038.abstract
AB 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 StatementT.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.