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

Fingerprint

Ewing's Sarcoma
Apoptosis
Oncogene Fusion
Histone Code
RNA Sequence Analysis
Biological Phenomena
Bone Neoplasms
Inborn Genetic Diseases
Biological Products
Microtubules
Pharmaceutical Preparations
Computer Simulation
Cell Survival
Therapeutics
EWS-FLI fusion protein
Pediatrics
Research
Genes

Keywords

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

Cite this

Tsafou, Kalliopi ; Katschnig, Anna Maria ; Radic-Sarikas, Branka ; Mutz, Cornelia Noëlle ; Iljin, Kristiina ; Schwentner, Raphaela ; Kauer, Maximilian O. ; Mühlbacher, Karin ; Aryee, Dave N.T. ; Westergaard, David ; Haapa-Paananen, Saija ; Fey, Vidal ; Superti-Furga, Giulio ; Toretsky, Jeffrey ; Brunak, Søren ; Kovar, Heinrich. / Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers. In: Oncotarget. 2018 ; Vol. 9, No. 57. pp. 31018-31031.
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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.",
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Tsafou, K, Katschnig, AM, Radic-Sarikas, B, Mutz, CN, Iljin, K, Schwentner, R, Kauer, MO, Mühlbacher, K, Aryee, DNT, Westergaard, D, Haapa-Paananen, S, Fey, V, Superti-Furga, G, Toretsky, J, Brunak, S & Kovar, H 2018, 'Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers', Oncotarget, vol. 9, no. 57, pp. 31018-31031. https://doi.org/10.18632/oncotarget.25760

Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers. / Tsafou, Kalliopi (Corresponding Author); Katschnig, Anna Maria (Corresponding Author); Radic-Sarikas, Branka (Corresponding Author); Mutz, Cornelia Noëlle; Iljin, Kristiina; Schwentner, Raphaela; Kauer, Maximilian O.; Mühlbacher, Karin; Aryee, Dave N.T.; Westergaard, David; Haapa-Paananen, Saija; Fey, Vidal; Superti-Furga, Giulio; Toretsky, Jeffrey; Brunak, Søren; Kovar, Heinrich.

In: Oncotarget, Vol. 9, No. 57, 24.07.2018, p. 31018-31031.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Tsafou, Kalliopi

AU - Katschnig, Anna Maria

AU - Radic-Sarikas, Branka

AU - Mutz, Cornelia Noëlle

AU - Iljin, Kristiina

AU - Schwentner, Raphaela

AU - Kauer, Maximilian O.

AU - Mühlbacher, Karin

AU - Aryee, Dave N.T.

AU - Westergaard, David

AU - Haapa-Paananen, Saija

AU - Fey, Vidal

AU - Superti-Furga, Giulio

AU - Toretsky, Jeffrey

AU - Brunak, Søren

AU - Kovar, Heinrich

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N2 - 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.

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