Abstract
Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15% of all pediatric cancer-related deaths. New therapies are needed to improve outcomes for children with high-risk and relapsed tumors. Inhibitors of the RET kinase and the RAS-MAPK pathway have previously been shown to be effective against neuroblastoma, suggesting that combined inhibition may have increased efficacy. RXDX-105 is a small molecule inhibitor of multiple kinases, including the RET and BRAF kinases. We found that treatment of neuroblastoma cells with RXDX-105 resulted in a significant decrease in cell viability and proliferation in vitro and in tumor growth and tumor vascularity in vivo. Treatment with RXDX-105 inhibited RET phosphorylation and phosphorylation of the MEK and ERK kinases in neuroblastoma cells and xenograft tumors, and RXDX-105 treatment induced both apoptosis and cell cycle arrest. RXDX-105 also showed enhanced efficacy in combination with 13-cis-retinoic acid, which is currently a component of maintenance therapy for children with high-risk neuroblastoma. Our results demonstrate that RXDX-105 shows promise as a novel therapeutic agent for children with high-risk and relapsed neuroblastoma.
Original language | English (US) |
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Pages (from-to) | 6323-6333 |
Number of pages | 11 |
Journal | Oncotarget |
Volume | 10 |
Issue number | 59 |
DOIs | |
State | Published - 2019 |
Keywords
- BRAF
- CEP-32496
- Neuroblastoma
- RET
- RXDX-105
ASJC Scopus subject areas
- Oncology