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Pharmaceutical-Grade Rigosertib Is a Microtubule-Destabilizing Agent

2020; Elsevier BV; Volume: 79; Issue: 1 Linguagem: Inglês

10.1016/j.molcel.2020.06.008

1097-4164

Marco Jost, Yuwen Chen, Luke A. Gilbert, Max A. Horlbeck, Lenno Krenning, Grégory Menchon, Ankit Rai, Min Y. Cho, Jacob J. Stern, A.E. Prota, Martin Kampmann, Anna Akhmanova, Michel O. Steinmetz, Marvin E. Tanenbaum, Jonathan S. Weissman,

Cancer Treatment and Pharmacology

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., 2020Baker S.J. Cosenza S.C. Athuluri-Divakar S. Reddy M.V.R. Vasquez-Del Carpio R. Jain R. Aggarwal A.K. Reddy E.P. A Contaminant Impurity, Not Rigosertib, Is a Tubulin Binding Agent.Mol. Cell. 2020; 79 (this issue): 180-190Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 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.