Blocking the road, stopping the engine or killing the driver? Advances in targeting EWS/FLI-1 fusion in Ewing sarcoma as novel therapy

Expert Opin Ther Targets. 2014 Nov;18(11):1315-28. doi: 10.1517/14728222.2014.947963. Epub 2014 Aug 27.


Introduction: Ewing sarcoma (ES) represents the paradigm of an aberrant E-twenty-six (ETS) oncogene-driven cancer. It is characterized by specific rearrangements of one of five alternative ETS family member genes with EWSR1. There is experimental evidence that the resulting fusion proteins act as aberrant transcription factors driving ES pathogenesis. The transcriptional gene regulatory network driven by EWS-ETS proteins provides the oncogenic engine to the tumor. Therefore, EWS-ETS and their downstream machinery are considered ideal tumor-specific therapeutic targets.

Areas covered: This review critically discusses the literature on the development of EWS-ETS-directed ES targeting strategies considering current knowledge of EWS-ETS biology and cellular context. It focuses on determinants of EWS-FLI1 function with an emphasis on interactions with chromatin structure. We speculate about the relevance of poorly investigated aspects in ES research such as chromatin remodeling and DNA damage repair for the development of targeted therapies.

Expert opinion: This review questions the specificity of signature-based screening approaches to the identification of EWS-FLI1-targeted compounds. It challenges the view that targeting the downstream gene regulatory network carries potential for therapeutic breakthroughs because of resistance-inducing network rewiring. Instead, we propose to combine targeting of the fusion protein with epigenetic therapy as a future treatment strategy in ES.

Keywords: ETS; Ewing sarcoma; YK-4-279; cell cycle; chromatin; drug screening; epigenetics; mesenchymal stem cells; micro satellites; neural crest stem cells; pediatric oncology; transcription factor.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / pathology
  • Chromatin Assembly and Disassembly / physiology
  • DNA Repair / physiology
  • Drug Design
  • Epigenesis, Genetic
  • Humans
  • Molecular Targeted Therapy
  • Oncogene Proteins, Fusion / metabolism*
  • Proto-Oncogene Protein c-fli-1 / metabolism*
  • RNA-Binding Protein EWS / metabolism*
  • Sarcoma, Ewing / drug therapy*
  • Sarcoma, Ewing / genetics
  • Sarcoma, Ewing / pathology


  • Antineoplastic Agents
  • EWS-FLI fusion protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS