Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells

Neoplasia. 2011 Feb;13(2):145-53. doi: 10.1593/neo.101202.


ET-743 (trabectedin; Yondelis) is approved in Europe for the treatment of soft tissue sarcomas. Emerging phase 1 and 2 clinical data have shown high response rates in myxoid liposarcoma in part owing to the inhibition of the FUS-CHOP transcription factor. In this report, we show that modulation of specific oncogenic transcription factors by ET-743 may extend to other tumor types. We demonstrate that, among a panel of pediatric sarcomas, Ewing sarcoma family of tumors (ESFTs) cell lines bearing the EWS-FLI1 transcription factor are the most sensitive to treatment with ET-743 compared with osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. We show that ET-743 reverses a gene signature of induced downstream targets of EWS-FLI1 in two different ESFT cell lines (P = .001). In addition, ET-743 directly suppresses the promoter activity of a known EWS-FLI1 downstream target NR0B1 luciferase reporter construct without changing the activity of a constitutively active control in ESFT cells. Furthermore, the effect is specific to EWS-FLI1, as forced expression of EWS-FLI1 in a cell type that normally lacks this fusion protein, HT1080 cells, induces the same NR0B1 promoter, but this activation is completely blocked by ET-743 treatment. Finally, we used gene set enrichment analysis to confirm that other mechanisms of ET-743 are active in ESFT cells. These results suggest a particular role for ET-743 in the treatment of translocation-positive tumors. In addition, the modulation of EWS-FLI1 makes it a novel targeting agent for ESFT and suggests that further development of this compound for the treatment of ESFT is warranted.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Bone Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Child
  • DAX-1 Orphan Nuclear Receptor / drug effects
  • DAX-1 Orphan Nuclear Receptor / genetics
  • Dioxoles / therapeutic use*
  • Europe
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / drug effects
  • Oncogene Proteins, Fusion / metabolism
  • Promoter Regions, Genetic / drug effects
  • Proto-Oncogene Protein c-fli-1 / antagonists & inhibitors*
  • Proto-Oncogene Protein c-fli-1 / metabolism
  • RNA-Binding Protein EWS / antagonists & inhibitors*
  • RNA-Binding Protein EWS / metabolism
  • RNA-Binding Protein FUS / drug effects
  • Sarcoma / drug therapy
  • Sarcoma, Ewing / drug therapy*
  • Tetrahydroisoquinolines / therapeutic use*
  • Trabectedin
  • Transcription Factor CHOP / drug effects


  • Antineoplastic Agents, Alkylating
  • DAX-1 Orphan Nuclear Receptor
  • Dioxoles
  • EWS-FLI fusion protein
  • NR0B1 protein, human
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • RNA-Binding Protein FUS
  • TLS-CHOP fusion protein, human
  • Tetrahydroisoquinolines
  • Transcription Factor CHOP
  • Trabectedin