Therapeutic targeting of KDM1A/LSD1 in Ewing sarcoma engages the ER-stress response I

The purpose of this study was to define biomarkers of sensitivty and mechanisms of resistance to the KDM1A/LSD1 inhibtor SP-2509 (HCI-2509) in Ewing sarcoma cell lines. We report that regardless of drug sensitivity all cell lines engage the UPR and ER-stress response following treatment with SP-2509 resulting in apoptotic cytotoxicity. In addition hypersentsitive cell lines shared a common basal transcriptnomic profile, with hypersensitive cell lines signficantly inducing ETS1 which was not observed in sensitive cell lines. Overall design: 6 Ewing sarcoma cell lines were treated with either vehicle control (DMSO) or the reversible LSD1/KDM1A inhibitor SP-2509 (2uM) for 48hrs. Three SP-2509 hypersensitive (IC50< 300nM)(A673, TC32, TC252) and three SP-2509 sensitive (IC50>900nM) (EWS-502, ES-2 and TC71) cell lines were investigated. Paired RNA from three indpendent experiments per cell line was analyzed.

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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