ArticleCancer medicine2023
Screening for DAX1/EWS-FLI1 functional inhibitors identified dihydroorotate dehydrogenase as a therapeutic target for Ewing's sarcoma.
Article in Cancer medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed, 7 citations in OpenAlex.
- Unlocking epigenetics for precision treatment of Ewing's sarcoma.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2024Article
- EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma.International journal of molecular sciences · 2023Review
- Screening for DAX1/EWS-FLI1 functional inhibitors identified dihydroorotate dehydrogenase as a therapeutic target for Ewing's sarcoma.Cancer medicine · 2023Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveEWS-FLI1 is the most common oncogenic fusion protein in Ewing's sarcoma family tumors (ESFTs). DAX1, an orphan member of the nuclear receptor superfamily, is up-regulated by EWS-FLI1 and plays a key role in the transformed phenotype of ESFTs.
methodsTo discover a functional inhibitor of DAX1 and EWS-FLI1, we screened small-molecular inhibitors using a DAX1 reporter assay system.
resultsK-234 and its derivatives, which were dihydroorotate dehydrogenase (DHODH) inhibitors, showed inhibitory effects in the reporter assay. K-234 inhibited the growth of Ewing's sarcoma with various fusion types, and K-234 derivatives altered the expression of EWS-FLI1-regulated genes. The DAX1 expression had no effect on the growth inhibitory effect of the K-234 derivatives, while DHODH overexpression or uridine treatment attenuated their inhibitory effects, suggesting that inhibition by K-234 derivatives occurs through DHODH inhibition. An in vivo study showed that a K-234 derivative clearly inhibited tumor growth in an Ewing's sarcoma xenograft mouse model.
conclusionTaken together, the present results suggest that DHODH inhibitors can inhibit the function of DAX1/EWS-FLI1 in ESFTs and might be a therapeutic agent with potent anti-tumor activity for Ewing's sarcoma patients.
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