{"entity":{"id":"ewsr1-fli1","kind":"target","name":"EWSR1-FLI1 fusion","aka":[],"tldr":"The fused gene that defines Ewing sarcoma: an aberrant transcription factor that has resisted 30 years of drug design.","summary":"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.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/EWS/FLI","links":[{"label":"Delattre 1992 (Nature)","url":"https://doi.org/10.1038/359162a0"}],"tags":["gap-fill"],"related":[],"cancers":["ewing-sarcoma","sarcoma"],"sections":[],"technologies":["protac-degrader","cytogenetics-fish","rna-seq"],"targets":[],"drugs":["lurbinectedin","trabectedin"],"companies":[],"institutions":[],"pathways":[],"terms":["gene-fusion"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-delattre-nature"],"journals":[],"dependsOn":[],"notes":[],"symbol":"EWSR1::FLI1","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"one-type","specificityNote":"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.)","specificitySources":[{"label":"Human Protein Atlas EWSR1 tissue","url":"https://www.proteinatlas.org/ENSG00000182944-EWSR1/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas FLI1 tissue","url":"https://www.proteinatlas.org/ENSG00000151702-FLI1/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000182944 associations","url":"https://platform.opentargets.org/target/ENSG00000182944/associations","note":"cancer associations at or above 0.5 (CC0)"},{"label":"Open Targets ENSG00000151702 associations","url":"https://platform.opentargets.org/target/ENSG00000151702/associations","note":"cancer associations at or above 0.5 (CC0)"}],"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.","whereFound":["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)"],"targetClass":"transcription","prevalence":[{"cancerId":"ewing-sarcoma","pct":"85","measure":"EWSR1-FLI1 fusion","source":"https://doi.org/10.1038/359162a0"}]},"route":"/targets/ewsr1-fli1/","neighbours":{"cancer":[{"id":"ewing-sarcoma","kind":"cancer","name":"Ewing sarcoma","route":"/cancers/ewing-sarcoma/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"technology":[{"id":"cytogenetics-fish","kind":"technology","name":"Cytogenetics and FISH","route":"/technologies/cytogenetics-fish/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"}],"drug":[{"id":"lurbinectedin","kind":"drug","name":"Lurbinectedin","route":"/drugs/lurbinectedin/"},{"id":"tk216","kind":"drug","name":"TK216","route":"/drugs/tk216/"},{"id":"trabectedin","kind":"drug","name":"Trabectedin","route":"/drugs/trabectedin/"}],"term":[{"id":"cytogenetics","kind":"term","name":"Cytogenetics and karyotype","route":"/terms/cytogenetics/"},{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"},{"id":"histological-response-induction","kind":"term","name":"Histological response to induction chemotherapy (osteosarcoma and Ewing sarcoma)","route":"/terms/histological-response-induction/"}],"paper":[{"id":"paper-delattre-nature","kind":"paper","name":"Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours","route":"/key-papers/paper-delattre-nature/"}],"pathway":[{"id":"oncogene-activation-two-hit","kind":"pathway","name":"Drivers, passengers & the two-hit model","route":"/pathways/oncogene-activation-two-hit/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}]}}