Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.
Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.
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DOI：
10.1158/1535-7163.mct-18-0373
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发表时间：
2018-09
影响因子：
5.7
通讯作者：
Lessnick SL
中科院分区：
文献类型：
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作者：
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
尤文肉瘤是儿童和青少年人群中第二常见的骨恶性肿瘤，多药化疗方案仍然是尤文肉瘤的基础治疗。我们已经达到了传统细胞毒性药物的治疗上限，强调需要采取新的方法，专门针对尤文肉瘤肿瘤发生的驱动程序。由于KDM 1A/LSD 1（赖氨酸特异性脱甲基酶1）在尤文肉瘤细胞系和肿瘤中高度表达，表达水平升高与总生存期变差相关（P=0.033），因此本研究检查了使用SP-2509（可逆性KDM 1A抑制剂）对靶向KDM 1A抑制的敏感性和细胞毒性机制的生物标志物。我们报告，在我们的尤文肉瘤细胞系队列（n=17）中未观察到对SP-2509的先天耐药性（IC 50范围为81 nM-1593 nM），相反，在多个细胞系中观察到对下一代KDM 1A不可逆抑制剂GSK-LSD 1的耐药性（IC 50>300μM）。虽然TP 53/STAG 2/CDKN 2A状态和基础KDM 1A mRNA和蛋白水平与SP-2509反应无关，但SP-2509治疗后KDM 1B的诱导与SP-2509超敏性密切相关。我们发现，SP-2509驱动的转录谱强烈反映了KDM 1A基因缺失。从机制上讲，RNA-seq分析揭示SP-2509通过参与内质网（ER）应激途径赋予稳健的细胞凋亡。此外，ETS 1/HIST 1H 2BM在SP-2509处理后仅在我们的过敏细胞系中分别被特异性诱导/抑制。总之，我们的研究结果为SP-2509细胞毒性机制以及可用于预测尤文肉瘤中KDM 1A抑制剂敏感性的生物标志物提供了关键见解。
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/LSD1 (Lysine Specific Demethylase 1) 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 81nM-1593nM), in contrast resistance to the next generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50>300μM). 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 hyper-sensitivity. 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 (ER) 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.