期刊
MOLECULAR CELL
卷 79, 期 1, 页码 191-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.06.008
关键词
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资金
- National Institutes of Health [P50 GM102706, U01 CA168370, R01 DA036858, F32 GM116331]
- Swiss National Science Foundation [31003A_166608]
- European Research Council [ERC-STG 677936-RNAREG, 609822 MODEL-CELL]
- Dutch Cancer Society (KWF)
- NWO CW ECHO grant [711.015.005]
- NIH/NCI [K99 CA204602, K99 CA181494]
- Stand Up to Cancer Innovative Research Grant
We recently used CRISPRi/a-based chemical-genetic screens and cell biological, biochemical, and structural assays to determine that rigosertib, an anti-cancer agent in phase III clinical trials, kills cancer cells by destabilizing microtubules. Reddy and co-workers (Baker et al., 2020, this issue of Molecular Cell) suggest that a contaminating degradation product in commercial formulations of rigosertib is responsible for the microtubule-destabilizing activity. Here, we demonstrate that cells treated with pharmaceutical-grade rigosertib (>99.9% purity) or commercially obtained rigosertib have qualitatively indistinguishable phenotypes across multiple assays. The two formulations have indistinguishable chemical-genetic interactions with genes that modulate microtubule stability, both destabilize microtubules in cells and in vitro, and expression of a rationally designed tubulin mutant with a mutation in the rigosertib binding site (L240F TUBB) allows cells to proliferate in the presence of either formulation. Importantly, the specificity of the L240F TUBB mutant for microtubule-destabilizing agents has been confirmed independently. Thus, rigosertib kills cancer cells by destabilizing microtubules, in agreement with our original findings.
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