EWS-FLI1 and RNA helicase A interaction inhibitor YK-4-279 inhibits growth of neuroblastoma.

Wenjing Sun,Yesenia Rojas,Sanjeev A Vasudevan,Jason M Shohet,Yanling Zhao,Cristian Coarfa,Angela Major,Saurabh Agarwal,Yongfeng Wang,Jianhua Yang,Xin Xu,Zhenghu Chen,Jingling Jin,Hao Wang,Hong Zhang,Wei Huang,Jed G Nuchtern,Roma H Patel ,M John Hicks ,Yu Ye ,Kimal I Rajapakshe ,Sarah E Woodfield

doi:10.18632/oncotarget.21933

Abstract

Treatment failure in high risk neuroblastoma (NB) is largely due to the development of chemotherapy resistance. We analyzed the gene expression changes associated with exposure to chemotherapy in six high risk NB tumors with the aid of the Connectivity Map bioinformatics platform. Ten therapeutic agents were predicted to have a high probability of reversing the transcriptome changes associated with neoadjuvant chemotherapy treatment. Among these agents, initial screening showed the EWS-FLI1 and RNA helicase A interaction inhibitor YK-4-279, had obvious cytotoxic effects on NB cell lines. Using a panel of NB cell lines, including MYCN nonamplified (SK-N-AS, SH-SY5Y, and CHLA-255), and MYCN amplified (NB-19, NGP, and IMR-32) cell lines, we found that YK-4-279 had cytotoxic effects on all lines tested. In addition, YK-4-279 also inhibited cell proliferation and anchorage-independent growth and induced cell apoptosis of these cells. YK-4-279 enhanced the cytotoxic effect of doxorubicin (Dox). Moreover, YK-4-279 was able to overcome the established chemoresistance of LA-N-6 NB cells. In an orthotopic xenograft NB mouse model, YK-4-279 inhibited NB tumor growth and induced apoptosis in tumor cells through PARP and Caspase 3 cleavage in vivo. While EWS-FLI1 fusion protein is not frequently found in NB, using the R2 public database of neuroblastoma outcome and gene expression, we found that high expression of EWSR1 was associated with poor patient outcome. Knockdown of EWSR1 inhibited the oncogenic potential of neuroblastoma cell lines. Taken together, our results indicate that YK-4-279 might be a promising agent for treatment of NB that merits further exploration.

Highlights

IntroductionMore than 650 cases are diagnosed each year in North America
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood
We have demonstrated that the EWS-FLI1 and RNA helicase A (RHA) interaction inhibitor YK-4-279 is active against neuroblastoma cell lines in vitro and in a mouse xenograft model of NB

Summary

Introduction

More than 650 cases are diagnosed each year in North America. It causes up to 10% of childhood cancer mortality while accounting for about 5% of all pediatric cancer diagnoses. In spite of intensive multimodal therapy, the 5-year survival rate in children with high-risk disease is approximately 40% and has not improved dramatically over the past two decades [1,2,3,4,5,6]. The understanding of NB and new drug discovery have advanced tremendously with the help of molecular genetic techniques like genome sequencing and bioinformatic analysis, a detailed understanding of the pathogenesis of chemotherapy resistance in this pediatric cancer remains obscure [7, 8]

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Results

Conclusion