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Published on: August 25, 2023
Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in
Kelli L Goss1, David J Gordon1
1Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA.
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.
Insights
Researchers identified iron chelators as a potential therapy for Ewing sarcoma by targeting the EWS-FLI1 protein. Inhibiting ribonucleotide reductase (RNR) showed promise in reducing tumor growth and increasing cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ewing sarcoma is an aggressive cancer driven by the EWS-FLI1 fusion protein.
- Targeting EWS-FLI1 directly is challenging, necessitating alternative strategies like targeting its downstream mediators.
- There is a need for targeted therapies with improved efficacy and reduced toxicity compared to conventional chemotherapy.
Purpose of the Study:
- To identify novel therapeutic strategies for Ewing sarcoma by targeting EWS-FLI1 dependencies.
- To investigate the potential of iron chelators as a therapeutic approach for Ewing sarcoma.
- To identify key mediators of EWS-FLI1 function and drug sensitivity.
Main Methods:
- Utilized gene expression data from a Ewing sarcoma model to screen drugs using the Connectivity Map.
- Identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as a key target.
- Assessed the effects of RNR inhibition on Ewing sarcoma cells in vitro and in vivo xenograft models.
- Investigated the role of SLFN11 in mediating sensitivity to RNR inhibition.
Main Results:
- Iron chelators were identified as drugs that downregulate EWS-FLI1 target genes.
- Inhibition of RNR led to apoptosis in Ewing sarcoma cells and reduced tumor growth in vivo.
- High SLFN11 levels were found to mediate sensitivity to RNR inhibition in Ewing sarcoma cells.
- Demonstrated a unique dependency of Ewing sarcoma on RNR.
Conclusions:
- Ribonucleotide reductase (RNR) is a critical dependency in Ewing sarcoma.
- RNR inhibitors, already in clinical use, represent a promising novel therapeutic strategy for Ewing sarcoma.
- The findings support further clinical investigation of RNR inhibitors for Ewing sarcoma treatment.
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