Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response
Year: 2018
Type: article
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.
Source: Molecular Cancer Therapeutics
Institutions: Nationwide Children's Hospital, Abigail Wexner Research Institute, The University of Adelaide, The Ohio State University, University of Utah, Huntsman Cancer Institute, Harvard University, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, University of Michigan, Michigan Medicine, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Hospital Sant Joan de Déu Barcelona, Université Paris Sciences et Lettres, Institut Curie, Translational Genomics Research Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1504112592, EWS/FLI AND ITS TARGETS IN EWING'S SARCOMA, G3738494541, G421865639, Children's Oncology Group Statistics and Data Center, Pre-clinical Evaluation of the LSD1 Inhibitor HCI-2509: Defining the Biomarkers of Sensitivity and the Mechanisms of Resistance, G6128235484, G7053914747, G8519683936, G858682239, G9000018419, Cancer Center Support Grant
OpenAlex ID: W2824417389