Patrick Grohar
Faculty Member
Last active: 3/27/2014

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

Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, Khan J, Helman LJ
Neoplasia. 2011 13 (2): 145-53

PMID: 21403840 · PMCID: PMC3033593 · 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.

MeSH Terms (20)

Antineoplastic Agents, Alkylating Bone Neoplasms Cell Line, Tumor Child DAX-1 Orphan Nuclear Receptor Dioxoles Europe Gene Expression Regulation, Neoplastic Humans Oncogene Proteins, Fusion Promoter Regions, Genetic Proto-Oncogene Protein c-fli-1 RNA-Binding Protein EWS RNA-Binding Protein FUS Sarcoma Sarcoma Sarcoma, Ewing Tetrahydroisoquinolines Trabectedin Transcription Factor CHOP

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