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|Ref Type||Journal Article|
|Authors||Pishas KI, Drenberg CD, Taslim C, Theisen ER, Johnson KM, Saund RS, Pop IL, Crompton BD, Lawlor ER, Tirode F, Mora J, Delattre O, Beckerle MC, Callen DF, Sharma S, Lessnick SL|
|Title||Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|GSK-LSD1||KDM1A Inhibitor 12||GSK-LSD1 is an irreversible KDM1A inhibitor that covalently binds to the FAD pocket and blocks enzymatic activity of KDM1A, thereby potentially inhibiting cell viability and tumor growth (PMID: 29997151, PMID: 26175415).|
|SP-2509||SP2509|HCI2509|HCI-2509||KDM1A Inhibitor 12||SP-2509 is a small molecule that selectively inhibits KDM1A, which potentially results in increased apoptosis and inhibition of colony formation, cell viability, and tumor growth (PMID: 29997151, PMID: 24699304, PMID: 24963049).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Ewing sarcoma||not applicable||SP-2509||Preclinical - Cell culture||Actionable||In a preclinical study, EWS fusion-positive Ewing sarcoma cell lines demonstrated reduced viability following SP-2509 treatment that correlated with induction of KDM1B expression post-treatment in culture (PMID: 29997151).||29997151|
|Unknown unknown||Ewing sarcoma||no benefit||GSK-LSD1||Preclinical - Cell culture||Actionable||In a preclinical study, Ewing sarcoma cell lines did not demonstrate sensitivity to GSK-LSD1 in culture (PMID: 29997151).||29997151|
|Unknown unknown||Ewing sarcoma||no benefit||Tranylcypromine||Preclinical - Cell culture||Actionable||In a preclinical study, Ewing sarcoma cell lines did not demonstrate sensitivity to Parnate (tranylcypromine) in culture (PMID: 29997151).||29997151|
|Unknown unknown||rhabdomyosarcoma||not applicable||SP-2509||Preclinical - Cell culture||Actionable||In a preclinical study, SP-2509 treatment inhibited viability of rhabdomyosarcoma cell lines in culture (PMID: 29997151).||29997151|
|Unknown unknown||osteosarcoma||not applicable||SP-2509||Preclinical - Cell culture||Actionable||In a preclinical study, SP-2509 treatment inhibited viability of osteosarcoma cell lines in culture (PMID: 29997151).||29997151|