title: Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma.
abstract: There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells caused apoptosis in vitro and attenuated tumor growth in an in vivo, xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further investigation of RNR inhibitors, which are currently used in clinical practice, as a novel approach for treating Ewing sarcoma.
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Goss
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gordon
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000077768:Ciclopirox; D003001:Cloning, Molecular; D004249:DNA Damage; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000235:genetics*; D016196:S Phase; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D000093542:Gemcitabine
chemical_list: C106031:EWS-FLI fusion protein; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D011728:Pyridones; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS; C576668:SLFN11 protein, human; D003841:Deoxycytidine; D000077768:Ciclopirox; D012264:Ribonucleotide Reductases; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine
keywords: Ewing sarcoma; ciclopirox; iron chelator; ribonucleotide reductase