title: Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells.
abstract: 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.
authors.affiliation: Molecular Oncology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA. groharp@mail.nih.gov
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Grohar
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Griffin
authors.forename: Choh
authors.initials: C
authors.lastname: Yeung
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Chen
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002648:Child; D057137:DAX-1 Orphan Nuclear Receptor / Q000187:drug effects / Q000235:genetics; D004149:Dioxoles / Q000627:therapeutic use*; D005060:Europe; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000187:drug effects; D012509:Sarcoma / Q000188:drug therapy; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D000077606:Trabectedin; D051742:Transcription Factor CHOP / Q000187:drug effects
chemical_list: D018906:Antineoplastic Agents, Alkylating; D057137:DAX-1 Orphan Nuclear Receptor; D004149:Dioxoles; C106031:EWS-FLI fusion protein; C539965:NR0B1 protein, human; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; C106030:TLS-CHOP fusion protein, human; D044005:Tetrahydroisoquinolines; D051742:Transcription Factor CHOP; D000077606:Trabectedin