VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells
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 nu...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Elsevier BV
2020
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| Online Access: | https://hdl.handle.net/1721.1/124625 |
| _version_ | 1826195920821157888 |
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| author | Patterson, Jesse C. Joughin, Brian A. Whitman, Matthew A. Varmeh, Shohreh Lauffenburger, Douglas A. Yaffe, Michael B. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Patterson, Jesse C. Joughin, Brian A. Whitman, Matthew A. Varmeh, Shohreh Lauffenburger, Douglas A. Yaffe, Michael B. |
| author_sort | Patterson, Jesse C. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:17:57Z |
| format | Article |
| id | mit-1721.1/124625 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:17:57Z |
| publishDate | 2020 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1246252022-09-30T20:14:35Z VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells Patterson, Jesse C. Joughin, Brian A. Whitman, Matthew A. Varmeh, Shohreh Lauffenburger, Douglas A. Yaffe, Michael B. Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT 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. National Institutes of Health (U.S.) (Grant R35-ES028374) National Institutes of Health (U.S.) (Grant R01-GM104047) National Institutes of Health (U.S.) (Grant R01-ES015339) National Institutes of Health (U.S.) (Grant U54-CA112967) National Institutes of Health (U.S.) (Grant U54-CA217377) American Cancer Society. Post-Doctoral Fellowship (PF-13-355-01-TBE) National Cancer Institute (U.S.) (Support Grant P30-ES002109) 2020-04-14T15:46:13Z 2020-04-14T15:46:13Z 2019-07 2020-02-04T16:11:48Z Article http://purl.org/eprint/type/JournalArticle 2405-4712 https://hdl.handle.net/1721.1/124625 Patterson, Jesse C. et al. "VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells." Cell Systems 9 (2019): 74-92 © 2019 The Authors en 10.1016/j.cels.2019.05.009 Cell Systems Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Patterson, Jesse C. Joughin, Brian A. Whitman, Matthew A. Varmeh, Shohreh Lauffenburger, Douglas A. Yaffe, Michael B. VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells |
| title | VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells |
| title_full | VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells |
| title_fullStr | VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells |
| title_full_unstemmed | VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells |
| title_short | VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells |
| title_sort | visage reveals a targetable mitotic spindle vulnerability in cancer cells |
| url | https://hdl.handle.net/1721.1/124625 |
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