Pharmaceutical-Grade Rigosertib Is a Microtubule-Destabilizing Agent

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

doi:10.1016/j.molcel.2020.06.008

Cited by 33 publications

(34 citation statements)

References 26 publications

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“…Due to the small sample size of paired BRAF inhibitor samples from the BRAF inhibitor clinical trial, we could only identify a trend toward a correlation between CD40 + melanoma and patient survival, which warrants future trials to validate the role of CD40 + melanoma cells in treatment responses. Moreover, there is recent controversy around the microtubule-destabilizing activity of RGS preparations as to whether it is due to a contaminant or endogenous activity of RGS [ 67 , 68 ]. Of note, several clinical trials are investigating the effectiveness of combining microtubule inhibitors with ICB therapy in melanoma (NCT01827111, NCT00796991 and NCT02617849).…”

Section: Discussionmentioning

confidence: 99%

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade

et al. 2021

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Background While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy. Methods Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data. Results RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB. Conclusions Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone. Trial registration NCT01205815 (Sept 17, 2010). Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade

et al. 2021

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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%

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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“…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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Pharmaceutical-Grade Rigosertib Is a Microtubule-Destabilizing Agent

Abstract: Highlights d Pharmaceutical-grade rigosertib kills cells by destabilizing microtubules d Pharmaceutical-grade rigosertib destabilizes microtubules in cells and in vitro d A rigosertib-binding mutation in tubulin alleviates rigosertibmediated toxicity

Cited by 33 publications

References 26 publications

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade

Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade

Anti-tumor effects of rigosertib in high-risk neuroblastoma

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

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