Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy.

Research output: Contribution to journalArticle

Authors

  • Antonio Romo-Morales
  • Ewa Aladowicz
  • Julian Blagg
  • Susanne Gatz
  • Janet M. Shipley

Colleges, School and Institutes

External organisations

  • Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, U.K.
  • Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.

Abstract

Background: Ewing sarcoma and desmoplastic small round cell tumors (DSRCT) are rare and clinically aggressive sarcomas usually characterized by oncogenic fusion proteins involving EWS. Emerging studies of Ewing sarcoma have demonstrated EWS-FLI1-driven chromatin remodeling as a key aspect of tumorigenicity. In particular, the lysine-specific demethylase KDM1A/LSD1 is linked to transcriptional regulation of target genes orchestrated by the EWS portion of the fusion protein interacting with repressive chromatin-remodeling complexes. Consistent with this model, depletion of KDM1A supports it is a molecular therapeutic target in Ewing sarcoma cells, but effective drugs need to be identified. Procedure: A comprehensive phenotypic analysis of the effects of catalytic KDM1A inhibitors ORY-1001 and GSK2879552, including clinically relevant doses, was carried out in 2D and 3D spheroid models of Ewing sarcoma and DSRCT. Results: Catalytic inhibition of KDM1A did not affect cell viability in 2D and 3D assays and had no impact on invasion in a 3D assay. Conclusions: Overall, evidence presented here does not support inhibition of KDM1A catalytic demethylase activity as an effective therapeutic strategy for Ewing sarcoma or DSRCT. However, roles of KDM1A beyond its demethylase activity should be considered for these sarcomas.

Bibliographic note

Highly clinically relevant since catalytic KDM1A inhibitors are currently pursued for clinical application in Ewing sarcoma. I have initiated this project and convinced the team about the importance of the publication of this seemingly "negative" result. I am shared senior author on this work.

Details

Original languageEnglish
Article numbere27888
Number of pages9
JournalPediatric Blood & Cancer
Volume66
Issue number9
Publication statusPublished - Sep 2019

Keywords

  • 3D models, Ewing sarcoma, GSK2879552, KDM1A/LSD1, ORY-1001, histone demethylase