The multikinase inhibitor RXDX-105 is effective against neuroblastoma in vitro and in vivo.

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.

• Authors: Sean M Flynn, Jacqueline Lesperance, Andrew Macias, Nikki Phanhthilath, Megan Rose Paul, Jong Wook Kim, Pablo Tamayo, Peter E Zage
• Journal: Oncotarget (Oncotarget) Vol. 10 Issue 59 Pg. 6323-6333 (Oct 29 2019) ISSN: 1949-2553 [Electronic] United States
• PMID: 31695841 (Publication Type: Journal Article)
• Copyright: Copyright: © 2019 Flynn et al.