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- W2960155897 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." @default.
- W2960155897 created "2019-07-23" @default.
- W2960155897 creator A5000351848 @default.
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- W2960155897 date "2019-07-01" @default.
- W2960155897 modified "2023-10-16" @default.
- W2960155897 title "VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells" @default.
- W2960155897 cites W1516095885 @default.
- W2960155897 cites W1520923182 @default.
- W2960155897 cites W1524992328 @default.
- W2960155897 cites W1578932543 @default.
- W2960155897 cites W1582305847 @default.
- W2960155897 cites W1592483428 @default.
- W2960155897 cites W1767510440 @default.
- W2960155897 cites W1809723326 @default.
- W2960155897 cites W1951421707 @default.
- W2960155897 cites W1963597960 @default.
- W2960155897 cites W1965043429 @default.
- W2960155897 cites W1965048434 @default.
- W2960155897 cites W1972161591 @default.
- W2960155897 cites W1981258651 @default.
- W2960155897 cites W1982846895 @default.
- W2960155897 cites W1992724001 @default.
- W2960155897 cites W1994652412 @default.
- W2960155897 cites W1996999733 @default.
- W2960155897 cites W2003971089 @default.
- W2960155897 cites W2004142027 @default.
- W2960155897 cites W2005308681 @default.
- W2960155897 cites W2006401070 @default.
- W2960155897 cites W2009339798 @default.
- W2960155897 cites W2021568546 @default.
- W2960155897 cites W2026143081 @default.
- W2960155897 cites W2029108033 @default.
- W2960155897 cites W2031211461 @default.
- W2960155897 cites W2036176224 @default.
- W2960155897 cites W2041238848 @default.
- W2960155897 cites W2041647205 @default.
- W2960155897 cites W2042146481 @default.
- W2960155897 cites W2043398720 @default.
- W2960155897 cites W2044025814 @default.
- W2960155897 cites W2048446704 @default.
- W2960155897 cites W2048551141 @default.
- W2960155897 cites W2048938594 @default.
- W2960155897 cites W2050574264 @default.
- W2960155897 cites W2052674054 @default.
- W2960155897 cites W2060737851 @default.
- W2960155897 cites W2061921829 @default.
- W2960155897 cites W2066411725 @default.
- W2960155897 cites W2072010297 @default.
- W2960155897 cites W2083363702 @default.
- W2960155897 cites W2088891952 @default.
- W2960155897 cites W2092364334 @default.
- W2960155897 cites W2095072642 @default.
- W2960155897 cites W2099623371 @default.
- W2960155897 cites W2100906891 @default.
- W2960155897 cites W2101725260 @default.
- W2960155897 cites W2101955590 @default.
- W2960155897 cites W2103135438 @default.
- W2960155897 cites W2103726956 @default.
- W2960155897 cites W2108740119 @default.
- W2960155897 cites W2110411949 @default.
- W2960155897 cites W2117692326 @default.
- W2960155897 cites W2118629005 @default.
- W2960155897 cites W2120292596 @default.
- W2960155897 cites W2130410032 @default.
- W2960155897 cites W2134435289 @default.
- W2960155897 cites W2134590240 @default.
- W2960155897 cites W2140493627 @default.
- W2960155897 cites W2144081223 @default.
- W2960155897 cites W2146212019 @default.
- W2960155897 cites W2146453026 @default.
- W2960155897 cites W2147328441 @default.
- W2960155897 cites W2153959970 @default.
- W2960155897 cites W2156755609 @default.
- W2960155897 cites W2161687028 @default.
- W2960155897 cites W2167279371 @default.
- W2960155897 cites W2167815875 @default.
- W2960155897 cites W2173488267 @default.
- W2960155897 cites W2179237675 @default.
- W2960155897 cites W2180229411 @default.
- W2960155897 cites W2223501982 @default.
- W2960155897 cites W2281603397 @default.
- W2960155897 cites W2404941902 @default.
- W2960155897 cites W2482744592 @default.
- W2960155897 cites W2553658634 @default.
- W2960155897 cites W2579434845 @default.
- W2960155897 cites W2586265133 @default.
- W2960155897 cites W2612974116 @default.