Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma
| Autor: | Deborah K. Morrison, Simone Difilippantinio, Christine M. Heske, Kelli M. Wilson, Jinqui-Qiu Chen, Joshua Kowalczyk, Xiaolin Wan, Marielle E. Yohe, Lisa M. Miller Jenkins, Robert W. Robey, Dan L. Sackett, Craig J. Thomas, Kristine A. Isanogle, Xiaoling Luo, Christina Robinson, Paul A. Randazzo, Alexander E. Kelly, Ruibai Luo, Gaelyn C. Lyons, Arnulfo Mendoza, Devorah C. Gallardo, Edjay R. Hernandez |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Vinca genetic structures Glycine Apoptosis Spindle Apparatus Article 03 medical and health sciences Neuroblastoma 0302 clinical medicine Rhabdomyosarcoma Medicine Humans Sulfones Mitosis Trametinib biology business.industry MEK inhibitor Rigosertib biology.organism_classification medicine.disease 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research business |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 |
| Popis: | Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NBs) have a poor prognosis despite multimodality 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. Although 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. |
| Databáze: | OpenAIRE |
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