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Mol Cancer Ther. 2018 Sep;17(9):1902-1916. doi: 10.1158/1535-7163.MCT-18-0373. Epub 2018 Jul 11.

Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.

Author information

1
Cancer Therapeutics Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
2
Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
3
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio.
4
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
5
Huntsman Cancer Institute, School of Medicine, University of Utah, Salt Lake City, Utah.
6
Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
7
Harvard Medical School, Boston, Massachusetts.
8
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan.
9
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
10
Univ Lyon, Universite Claude Bernard Lyon, Centre Leon Berard, Cancer Research Center of Lyon, Lyon, France.
11
Department of Pediatric Hemato-Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
12
Institut Curie, PSL Research University, Service de Genetique, Pole de Medecine Diagnostique et Theranostique, Unité de Génétique Somatique, Paris, France.
13
TGen Clinical Sciences, Applied Cancer Research and Drug Discovery, Phoenix, Arizona.
14
Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio. Stephen.Lessnick@nationwidechildrens.org.
15
Division of Pediatric Hematology/Oncology/Bone Marrow Transplant, Ohio State University, Columbus, Ohio.

Abstract

Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine-specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 -1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 μmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902-16. ©2018 AACR.

PMID:
29997151
PMCID:
PMC6201274
[Available on 2019-09-01]
DOI:
10.1158/1535-7163.MCT-18-0373

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