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Cell Syst. 2019 Jul 24;9(1):74-92.e8. doi: 10.1016/j.cels.2019.05.009. Epub 2019 Jul 10.

VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells.

Author information

1
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland.
4
Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
6
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
7
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland; Biozentrum, University of Basel 4056 Basel, Switzerland.
8
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
9
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: myaffe@mit.edu.

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.

KEYWORDS:

MTH1; Plk1; TH588; anti-microtubule drugs; cancer therapy; chromosome alignment; chromosome congression; drug synergy; mitosis; tubulin

PMID:
31302152
PMCID:
PMC6688637
[Available on 2020-07-24]
DOI:
10.1016/j.cels.2019.05.009
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