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The fused gene that defines Ewing sarcoma: an aberrant transcription factor that has resisted 30 years of drug design.
The t(11;22) fusion joins the low-complexity prion-like domain of EWSR1 to the DNA-binding domain of FLI1, creating a neomorphic transcription factor that binds GGAA microsatellites, opens chromatin (with BAF complex) and reprograms the cell. It is present in ~85% of Ewing sarcoma (EWSR1-ERG in most of the rest) and is the sole recurrent driver. Direct inhibition attempts (TK216/mithramycin analogues, YK-4-279) failed clinically; indirect strategies target its dependencies: LSD1 (seclidemstat), PARP/DNA damage response (trabectedin, lurbinectedin, PARP inhibitors), cell-cycle (CDK4/6, WEE1), IGF-1R (antibodies failed), and degraders. Detection by FISH/RT-PCR/RNA-seq is diagnostic; fusion ctDNA is an emerging MRD marker.
In plain words · The fused gene that defines Ewing sarcoma: an aberrant transcription factor that has resisted 30 years of drug design.
The fused gene that defines Ewing sarcoma: an aberrant transcription factor that has resisted 30 years of drug design.
EWSR1-FLI1 is a fusion oncoprotein; the EWSR1 domain drives phase separation and recruits BAF, while the FLI1 ETS domain binds GGAA repeats to activate (e.g. NR0B1, NKX2-2) and, at canonical ETS sites, repress (e.g.
1 product aims at EWSR1-FLI1 fusion: small molecules. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
Broadly expressed or essential: HPA lists EWSR1 among essential proteins and finds the RNA at low tissue specificity; the 3 medicines aimed at it (Lurbinectedin, Trabectedin, TK216) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA EWSR1: RNA low tissue specificity; high antibody staining in 39 normal tissues; highest cancer staining lung cancer (5 of 12 high). HPA FLI1: RNA tissue enhanced (lymphoid tissue 66 nTPM); no normal tissue stained high. Distribution: 1 cancer family in the corpus carries a prevalence row, label threshold or catalogue link for it (Sarcomas (soft tissue, bone, GIST)); Open Targets associates it with 0 specific cancer types at or above 0.5. (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas EWSR1 tissue; Human Protein Atlas FLI1 tissue; Open Targets ENSG00000182944 associations; Open Targets ENSG00000151702 associations
EWSR1-FLI1 is a fusion oncoprotein; the EWSR1 domain drives phase separation and recruits BAF, while the FLI1 ETS domain binds GGAA repeats to activate (e.g. NR0B1, NKX2-2) and, at canonical ETS sites, repress (e.g. TGFBR2, IGFBP3) target genes.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adipose tissue, Caudate, Cerebral cortex, Hippocampus, Skeletal muscle, Soft tissue.
Medium only: colorectal cancer, liver cancer, lymphoma.
HPA EWSR1 tissue · HPA EWSR1 pathology · HPA protein class: Essential proteins
RNA: tissue enhanced (lymphoid tissue 66 nTPM), detected in many normal tissues.
No normal tissue stained high.
No cancer sample stained medium or high.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Ewing sarcoma | 85% | EWSR1-FLI1 fusion | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
TK216 was an attempt to hit the fusion protein that causes Ewing sarcoma directly, something long thought impossible for a transcription factor. In early trials with vincristine it produced a few responses but not enough to carry the drug forward.
Query for this target: (TITLE:"EWSR1-FLI1 fusion" OR ABSTRACT:"EWSR1-FLI1 fusion" OR TITLE:"EWSR1::FLI1" OR ABSTRACT:"EWSR1::FLI1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about EWSR1-FLI1 fusion, not a curated reading list.
Shares Cytogenetics and FISH, Ewing sarcoma, RNA sequencing & expression profiling, Sarcomas (soft tissue, bone, GIST).
Shares Lurbinectedin, Ewing sarcoma.
Shares Cytogenetics and FISH, Transcriptional machinery & addiction, Gene fusion, RNA sequencing & expression profiling.
Shares Cytogenetics and FISH, Transcriptional machinery & addiction, Gene fusion, RNA sequencing & expression profiling.
Shares Gene fusion, PROTACs & molecular glues (targeted protein degradation), Sarcomas (soft tissue, bone, GIST).
Shares Lurbinectedin, Ewing sarcoma, Sarcomas (soft tissue, bone, GIST).