Journal article
Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma
Oncotarget, Vol.7(39), pp.63003-63019
09/27/2016
DOI: 10.18632/oncotarget.11416
PMCID: PMC5325343
PMID: 27557498
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.
Details
- Title: Subtitle
- Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma
- Creators
- Kelli L. Goss - University of IowaDavid J. Gordon - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.7(39), pp.63003-63019
- DOI
- 10.18632/oncotarget.11416
- PMID
- 27557498
- PMCID
- PMC5325343
- NLM abbreviation
- Oncotarget
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Publisher
- Impact Journals LLC
- Number of pages
- 17
- Grant note
- K08CA160346 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) University of Iowa Dance Marathon Award University of Iowa Stead Family Research Award 5K08 CA160346-03 / NCI K08 award Holden Comprehensive Cancer Center ACS-IRG Seed Grant
- Language
- English
- Date published
- 09/27/2016
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984353825402771
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