The multikinase inhibitor RXDX-105 is effective against neuroblastoma<i>in vitro</i>and<i>in vivo</i>

Abstract

// Sean M. Flynn 1 , Jacqueline Lesperance 2 , Andrew Macias 2 , Nikki Phanhthilath 2 , Megan Rose Paul 2 , 3 , Jong Wook Kim 4 , Pablo Tamayo 4 and Peter E. Zage 2 , 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&#x0027;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: pzage@ucsd.edu Keywords: neuroblastoma; RXDX-105; CEP-32496; RET; BRAF Received: June 26, 2019&emsp;&emsp;&emsp;&emsp; Accepted: September 10, 2019&emsp;&emsp;&emsp;&emsp; 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.