Abstract 1955: Targeting ribonucleotide reductase (RNR) in Ewing sarcoma

Abstract

Abstract Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. The EWS-FLI1 oncoprotein functions, in part, as an aberrant transcription factor and is required for tumor growth and survival. In order to identify downstream targets of EWS-FLI1, we used human embryonic stem cells that express inducible EWS-FLI1 to model the initiation and development of Ewing sarcoma in a genetically defined system. We then used this model system and a gene expression based approach to identify that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), which impair DNA replication by blocking the synthesis of deoxyribonucleotides. Here we report that the treatment of Ewing sarcoma cells with gemcitabine, an irreversible inhibitor of the RRM1 subunit of RNR, results in impaired DNA replication, cell cycle arrest, and apoptosis in Ewing sarcoma cells. Additionally, we have found that the effect of gemcitabine on the viability of Ewing sarcoma cells is sustained even after removal of the drug from the cell culture medium. Moreover, ataxia telangiectasia and rad3-related protein (ATR) and checkpoint kinase 1 (CHK1) inhibitors increase the toxicity of gemcitabine in Ewing sarcoma cells by blocking the adaptive response to impaired DNA replication. Currently, ongoing work is focused on the in vivo testing of gemcitabine, alone and in combination with CHK1 and ATR inhibitors, as a novel therapeutic approach for the treatment of Ewing sarcoma. Citation Format: Kelli Goss, Stacia Koppenhafer, Kathryn Harmoney, David Gordon. Targeting ribonucleotide reductase (RNR) in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1955. doi:10.1158/1538-7445.AM2017-1955