Research Papers:
The multikinase inhibitor RXDX-105 is effective against neuroblastoma in vitro and in vivo
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Abstract
Sean M. Flynn1, Jacqueline Lesperance2, Andrew Macias2, Nikki Phanhthilath2, Megan Rose Paul2,3, Jong Wook Kim4, Pablo Tamayo4 and Peter E. Zage2,3,4
1 Department of Surgery, University of California San Diego, La Jolla, CA, USA
2 Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA, USA
3 Peckham Center for Cancer and Blood Disorders, Rady Children's Hospital, San Diego, CA, USA
4 Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
Correspondence to:
Peter E. Zage, | email: | [email protected] |
Keywords: neuroblastoma; RXDX-105; CEP-32496; RET; BRAF
Received: June 26, 2019 Accepted: September 10, 2019 Published: October 29, 2019
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.
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