VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells
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1-s2.0-S2405471219301905-main.pdf
Description
Published version
Size
7.08 MB
Format
Adobe PDF
Checksum (MD5)
7303ab29832aa0efa94edb659eec96a1
Author(s)
Patterson, Jesse C.
Joughin, Brian A.
Whitman, Matthew A.
Varmeh, Shohreh
Lauffenburger, Douglas A.
Yaffe, Michael B.
Date Issued
July 2019
Journal
Cell Systems
Publisher
Elsevier BV
Citation
Patterson, Jesse C. et al. "VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells." Cell Systems 9 (2019): 74-92 © 2019 The Authors
Version
Author's final manuscript
Abstract
There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, an MTH1 inhibitor that prevents detoxification of oxidized nucleotide triphosphates. This combination showed robust synergistic killing of cancer, but not normal, cells that, surprisingly, was MTH1-independent. To dissect the underlying synergistic mechanism, we developed VISAGE, a strategy integrating experimental synergy quantification with computational-pathway-based gene expression analysis. VISAGE predicted, and we experimentally confirmed, that this synergistic combination treatment targeted the mitotic spindle. Specifically, TH588 binding to β-tubulin impaired microtubule assembly, which when combined with Plk1 blockade, synergistically disrupted mitotic chromosome positioning to the spindle midzone. These findings identify a cancer-specific mitotic vulnerability that is targetable using Plk1 inhibitors with microtubule-destabilizing agents and highlight the general utility of the VISAGE approach to elucidate molecular mechanisms of drug synergy.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1016/j.cels.2019.05.009
