Anti-tumor effects of rigosertib in high-risk neuroblastoma |
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| Authors: | Katarzyna Radke,Karin Hansson,Jonas Sjö lund,Magdalena Wolska,Jenny Karlsson,Javanshir Esfandyari,Kristian Pietras,Kristina Aaltonen,David Gisselsson,Daniel Bexell |
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| Affiliation: | aDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden;bDivision of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden;cDepartment of Pathology, Laboratory Medicine, Medical Services, University Hospital, Lund, Sweden |
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| Abstract: | High-risk neuroblastoma has a poor prognosis despite intense treatment, demonstrating the need for new therapeutic strategies. Here we evaluated the effects of rigosertib (ON-01910.Na) in preclinical models of high-risk neuroblastoma. Among several hundred cancer cell lines representing 24 tumor types, neuroblastoma was the most sensitive to rigosertib. Treatment of MYCN-amplified neuroblastoma organoids resulted in organoid disintegration, decreased cell viability, and increased apoptotic cell death. Neuroblastoma response to rigosertib involved G2M cell cycle arrest and decreased phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204). Rigosertib delayed tumor growth and prolonged survival of mice carrying neuroblastoma MYCN-amplified PDX tumors (median survival: 31 days, treated; 22 days, vehicle) accompanied with increased apoptosis in treated tumors. We further identified vincristine and rigosertib as a potential promising drug combination treatment. Our results show that rigosertib might be a useful therapeutic agent for MYCN-amplified neuroblastomas, especially in combination with existing agents. |
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| Keywords: | Neuroblastoma Rigosertib ON-01910 ON-01910.Na Patient-derived xenografts |
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