Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers

Kalliopi Tsafou (Corresponding Author), Anna Maria Katschnig (Corresponding Author), Branka Radic-Sarikas (Corresponding Author), Cornelia Noëlle Mutz, Kristiina Iljin, Raphaela Schwentner, Maximilian O. Kauer, Karin Mühlbacher, Dave N.T. Aryee, David Westergaard, Saija Haapa-Paananen, Vidal Fey, Giulio Superti-Furga, Jeffrey Toretsky, Søren Brunak, Heinrich Kovar

Research output: Contribution to journalArticleScientificpeer-review

2 Citations (Scopus)

Abstract

Ewing sarcoma (EwS) is an aggressive pediatric bone cancer in need of more effective therapies than currently available. Most research into novel targeted therapeutic approaches is focused on the fusion oncogene EWSR1-FLI1, which is the genetic hallmark of this disease. In this study, a broad range of 3,325 experimental compounds, among them FDA approved drugs and natural products, were screened for their effect on EwS cell viability depending on EWS-FLI1 expression. In a networkbased approach we integrated the results from drug perturbation screens and RNA sequencing, comparing EWS-FLI1-high (normal expression) with EWS-FLI1-low (knockdown) conditions, revealing novel interactions between compounds and EWSFLI1 associated biological processes. The top candidate list of druggable EWS-FLI1 targets included genes involved in translation, histone modification, microtubule structure, topoisomerase activity as well as apoptosis regulation. We confirmed our in silico results using viability and apoptosis assays, underlining the applicability of our integrative and systemic approach. We identified differential sensitivities of Ewing sarcoma cells to BCL-2 family inhibitors dependent on the EWS-FLI1 regulome including altered MCL-1 expression and subcellular localization. This study facilitates the selection of effective targeted approaches for future combinatorial therapies of patients suffering from Ewing sarcoma.

Original languageEnglish
Pages (from-to)31018-31031
Number of pages14
JournalOncotarget
Volume9
Issue number57
DOIs
Publication statusPublished - 24 Jul 2018
MoE publication typeNot Eligible

Keywords

  • Apoptosis
  • BCL-2 inhibitors
  • Drug-target network
  • Ewing sarcoma
  • High-throughput compound screening

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