Molecular Cell
Volume 79, Issue 1, 2 July 2020, Pages 180-190.e4
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A Contaminant Impurity, Not Rigosertib, Is a Tubulin Binding Agent

https://doi.org/10.1016/j.molcel.2020.05.024Get rights and content
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Highlights

  • Rigosertib does not bind directly to tubulin

  • Rigosertib dos not inhibit tubulin polymerization

  • Expression of TUBB L240F does not confer resistance to rigosertib

  • A small percentage of rigosertib- and BI2536-treated TUBB L240F cells undergo senescence

Summary

Rigosertib is a styryl benzyl sulfone that inhibits growth of tumor cells and acts as a RAS mimetic by binding to Ras binding domains of RAS effectors. A recent study attributed rigosertib’s mechanism of action to microtubule binding. In that study, rigosertib was obtained from a commercial vendor. We compared the purity of clinical-grade and commercially sourced rigosertib and found that commercially sourced rigosertib contains approximately 5% ON01500, a potent inhibitor of tubulin polymerization. Clinical-grade rigosertib, which is free of this impurity, does not exhibit tubulin-binding activity. Cell lines expressing mutant β-tubulin have also been reported to be resistant to rigosertib. However, our study showed that these cells failed to proliferate in the presence of rigosertib at concentrations that are lethal to wild-type cells. Rigosertib induced a senescence-like phenotype in the small percentage of surviving cells, which could be incorrectly scored as resistant using short-term cultures.

Keywords

rigosertib
ON01910
ON01500
RAS
Ras binding domain
tubulin polymerization

Cited by (0)

3

Present address: Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

4

Present Address: Sandoz, a Novartis Company, 5200 Blue Lagoon Drive, Miami, FL 33126, USA

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Lead Contact