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Updated: Jan 23, 2026

Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays
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Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays

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

Antonio Romo-Morales1, Ewa Aladowicz1, Julian Blagg2

  • 1Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, UK.

Pediatric Blood & Cancer
|June 18, 2019
PubMed
Abstract

Insights

Catalytic inhibition of KDM1A did not impact cell viability or invasion in Ewing sarcoma and DSRCT models. Further research into KDM1A

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ewing sarcoma and desmoplastic small round cell tumors (DSRCT) are aggressive pediatric sarcomas driven by EWS fusion proteins.
  • EWS-FLI1 in Ewing sarcoma promotes tumorigenicity via chromatin remodeling, involving lysine-specific demethylase KDM1A (also known as LSD1).
  • KDM1A is a potential therapeutic target due to its role in regulating target genes via repressive chromatin complexes.

Purpose of the Study:

  • To evaluate the therapeutic potential of KDM1A catalytic inhibitors in Ewing sarcoma and DSRCT.
  • To assess the effects of ORY-1001 and GSK2879552 on cancer cell viability and invasion.

Main Methods:

  • Phenotypic analysis of KDM1A inhibitors ORY-1001 and GSK2879552.
  • Utilized 2D and 3D spheroid models of Ewing sarcoma and DSRCT.
  • Assessed cell viability and invasion at clinically relevant doses.

Main Results:

  • Catalytic inhibition of KDM1A did not affect cell viability in 2D and 3D assays.
  • No impact on tumor cell invasion was observed in 3D assays.
  • The tested KDM1A inhibitors demonstrated limited efficacy in these sarcoma models.

Conclusions:

  • Inhibition of KDM1A's catalytic demethylase activity is not a viable therapeutic strategy for Ewing sarcoma or DSRCT.
  • Further investigation is warranted to explore non-demethylase functions of KDM1A in these cancers.
  • Alternative therapeutic targets or strategies may be necessary for treating these rare sarcomas.
Keywords:
3D modelsEwing sarcomaGSK2879552KDM1A/LSD1ORY-1001histone demethylase

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