A Contaminant Impurity, Not Rigosertib, Is a Tubulin Binding Agent

Baker, Stacey J.; Cosenza, Stephen C.; Athuluri-Divakar, Saikrishna; Reddy, M. V. Ramana; Carpió, Rodrigo Vásquez-Del; Jain, Rinku; Aggarwal, Aneel K.; Reddy, E. Premkumar

doi:10.1016/j.molcel.2020.05.024

Cited by 16 publications

(14 citation statements)

References 13 publications

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“…Initial findings described rigosertib as a multi-kinase signaling inhibitor with effects on PLK1, PI3K pathways, and the RAF-MEK-ERK pathway [7] , [30] , [31] , [32] , but the precise mechanism of action of rigosertib is still being debated [11] , [12] , [13] . Our results showing decreased pAKT (Ser473) and pERK1/2 (Thr202/Tyr204) levels indicate the involvement of the AKT and RAS signaling pathways in its mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

“…Rigosertib has also been proposed to function as a RAS mimetic by affecting the RAS-binding domain of RAS effector proteins, thereby inhibiting MEK-ERK signaling [10] . However, recent studies have shown that rigosertib functions as a microtubule-destabilizing agent [11] , therefore its precise mechanism(s) of action remain a matter of debate [12] , [13] . Nevertheless, rigosertib has shown anti-tumor effects in preclinical in vivo models of solid tumors including breast, pancreatic [6] , colorectal, and lung cancer [10] .…”

Section: Introductionmentioning

confidence: 99%

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Anti-tumor effects of rigosertib in high-risk neuroblastoma

Radke

Hansson

Sjölund

et al. 2021

Translational Oncology

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Highlights Analysis of multiple tumor types reveal neuroblastoma sensitivity to rigosertib. Neuroblastoma 2D and 3D organoid models are sensitive to rigosertib. Rigosertib causes G2M cell cycle arrest rather than inhibition of Ras binding domains. Rigosertib prolongs survival of MYCN - amplified patient-derived xenograft tumors. Combination of rigosertib and vincristine is synergistic against neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-tumor effects of rigosertib in high-risk neuroblastoma

Radke

Hansson

Sjölund

et al. 2021

Translational Oncology

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“…The stress MAP kinases phosphorylate components of the RAS pathway, including Raf family members and SOS1, a RAS guanine nucleotide exchange factor, which further decreases signaling through the RAS/RAF/MEK/ERK MAP kinase pathway (3). The mitotic stress induced by rigosertib may be due to the fact that rigosertib, or a degradation product of rigosertib, binds to an intradimer site between α-and β-tubulin in a manner similar to colchicine, which prevents microtubule growth (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma

Kowalczyk

Wan

Hernandez

et al. 2021

Molecular Cancer Therapeutics

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Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NB) have a poor prognosis despite multi-modality therapy. In addition, the current standard of care for these cancers includes vinca alkaloids that have severe toxicity profiles, further underscoring the need for novel therapies for these malignancies. Here, we show that the small molecule rigosertib inhibits the growth of RMS and NB cell lines by arresting cells in mitosis, which leads to cell death. Our data indicate that rigosertib, like the vinca alkaloids, exerts its effects mainly by interfering with mitotic spindle assembly. While rigosertib has the ability to inhibit oncogenic RAS signaling, we provide evidence that rigosertib does not induce cell death through inhibition of the RAS pathway in RAS-mutated RMS and NB cells. However, the combination of rigosertib and the MEK inhibitor trametinib, which has efficacy in RAS-mutated tumors, synergistically inhibits the growth of an RMS cell line, suggesting a new avenue for combination therapy. Importantly, rigosertib treatment delays tumor growth and prolongs survival in a xenograft model of RMS. In conclusion, rigosertib, through its impact on the mitotic spindle, represents a potential therapeutic for RMS.

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“…In certain experiments, BMDMs were pretreated with 20 nM rigosertib for 1 h as previously described. 15 , 16 , 17 Then these BMDMs were further treated with 100 ng/ml LPS, 20 µg/ml poly I:C or 10 µg/ml interleukin‐4 (IL‐4) for 12 or 24 h.…”

Section: Methodsmentioning

confidence: 99%

Rigosertib inhibits MEK1–ERK pathway and alleviates lipopolysaccharide‐induced sepsis

Wang

Jiang

2021

Immunity Inflam & Disease

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Background Here, by using the lipopolysaccharide (LPS)‐induced mice sepsis model, we treated septic wild‐type (WT) mice or MEK1DD mice with rigosertib to evaluate its prospective effects on sepsis. Methods We also generated macrophages derived from bone marrow from WT or MEK1DD mice. These macrophages were pretreated with rigosertib and then induced with LPS or poly I:C. Results Rigosertib suppressed LPS or poly I:C‐induced expression of inflammatory cytokines (tumor necrosis factor‐alpha [TNF‐α] and interleukin‐6 [IL‐6], and IL‐23) in WT bone marrow–derived macrophages while failed to affect the upregulation of TNF‐α and IL‐6 in LPS‐treated bone marrow–derived macrophages from MEK1DD mice. Rigosertib promoted survival rate, ameliorated lung injury, and reduced inflammatory cytokine levels in serum of WT septic mice. Conclusion In contrast, the effects of rigosertib on sepsis were abrogated in septic MEK1DD mice, which had inducible constitutive activation of MEK1 signaling. Rigosertib alleviated LPS‐induced sepsis inhibits MEK1/ERK signaling pathway.

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A Contaminant Impurity, Not Rigosertib, Is a Tubulin Binding Agent

Abstract: Highlights d Rigosertib does not bind directly to tubulin d Rigosertib dos not inhibit tubulin polymerization d Expression of TUBB L240F does not confer resistance to rigosertib d A small percentage of rigosertib-and BI2536-treated TUBB L240F cells undergo senescence

Cited by 16 publications

References 13 publications

Anti-tumor effects of rigosertib in high-risk neuroblastoma

Anti-tumor effects of rigosertib in high-risk neuroblastoma

Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma

Rigosertib inhibits MEK1–ERK pathway and alleviates lipopolysaccharide‐induced sepsis

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