Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy.
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ICR Authors
Authors
Romo-Morales, A
Aladowicz, E
Blagg, J
Gatz, SA
Shipley, JM
Aladowicz, E
Blagg, J
Gatz, SA
Shipley, JM
Document Type
Journal Article
Date
2019-09-01
Date Accepted
2019-05-31
Date Available
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.
Citation
Pediatric blood & cancer, 2019, 66 (9), pp. e27888 - ?
Source Title
Publisher
WILEY
ISSN
1545-5009
eISSN
1545-5017
Collections
Research Team
Sarcoma Molecular Pathology