EWSR1-FLI1 fusion
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.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · The fused gene that defines Ewing sarcoma: an aberrant transcription factor that has resisted 30 years of drug design.
- 1 · What it is
The fused gene that defines Ewing sarcoma: an aberrant transcription factor that has resisted 30 years of drug design.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
No product in this corpus aims at EWSR1-FLI1 fusion yet. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
Biology
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.
- Ewing sarcoma (~85%)
- EWSR1 fusions with other partners define desmoplastic small round cell tumour (EWSR1-WT1), clear cell sarcoma (EWSR1-ATF1), myxoid liposarcoma (FUS/EWSR1-DDIT3)
How common it is, by cancer
| 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.
Latest papers
topQuery 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.
Pages like this
not linked directly; found by shared links- ProductCrizotinib
Shares Gene fusion, Sarcomas (soft tissue, bone, GIST) and the tag gap-fill.
- ProductLarotrectinib
Shares Gene fusion, Sarcomas (soft tissue, bone, GIST) and the tag gap-fill.
- ProductEntrectinib
Shares Gene fusion, Sarcomas (soft tissue, bone, GIST) and the tag gap-fill.
- ProductTaletrectinib
Shares Gene fusion and the tag gap-fill.
- TargetMDM2
Shares PROTACs & molecular glues (targeted protein degradation), Sarcomas (soft tissue, bone, GIST) and the tag gap-fill.
- ProductPomalidomide
Shares PROTACs & molecular glues (targeted protein degradation) and the tag gap-fill.
- ProductPexidartinib
Shares Sarcomas (soft tissue, bone, GIST) and the tag gap-fill.
- TargetPRMT5 (MTAP-deleted cancers)
Shares Drivers, passengers & the two-hit model and the tag gap-fill.