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The Kinase Inhibitor GNF-7 Is Synthetically Lethal in Topoisomerase 1-Deficient Ewing Sarcoma
Carly M Sayers1, Morgan B Carter1, Haiyan Lei1
1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cancers
|August 14, 2025
Summary
A new molecule, GNF-7, shows promise for treating Ewing sarcoma (ES) by targeting TOP1-deficient cells. This discovery offers hope for patients with relapsed or resistant ES, especially when combined with existing therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Ewing sarcoma (ES) is an aggressive pediatric cancer driven by the EWS::FLI1 oncoprotein.
- Current treatments for metastatic or relapsed ES have limited long-term efficacy.
- Topoisomerase 1 (TOP1) inhibitors are standard therapies for relapsed ES.
Purpose of the Study:
- To identify mechanisms of resistance to TOP1 inhibitors in ES.
- To discover novel small molecules effective against ES, particularly in resistant contexts.
Main Methods:
- Genome-wide CRISPR knockout library screen to identify TOP1 deletion as a resistance mechanism.
- High-throughput small-molecule screen using isogenic cell lines.
- Characterization of GNF-7's molecular targets and activity.
Main Results:
- Deletion of TOP1 confers resistance to TOP1 inhibitors.
- GNF-7 exhibits significantly higher potency in TOP1-deficient ES cells.
- GNF-7 inhibits key kinases (CSK, p38α, EphA2, Lyn, ZAK) and downregulates EWS::FLI1-induced genes.
Conclusions:
- GNF-7 is a potential therapeutic agent for ES, especially in TOP1-resistant cases.
- Small molecules with similar kinase profiles may overcome TOP1 inhibitor resistance.
- Combination therapy with GNF-7 and TOP1 inhibitors warrants further investigation for ES treatment.
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