Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis. Our analyses revealed that LSD1 bound to the NOTCH1 locus, thereby suppressing NOTCH1 expression and downstream signaling. Reactivation of NOTCH signaling with the LSD1 inhibitor reduced the expression of ASCL1 and neuroendocrine cell lineage genes. Knockdown studies confirmed the pharmacological inhibitor-based results. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlated with the extent of consequential NOTCH pathway activation and repression of a neuroendocrine phenotype. Complete and durable tumor regression occurred with ORY-1001-induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.

中文翻译：

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通过LSD1抑制靶向小细胞肺癌中的NOTCH激活。

小细胞肺癌（SCLC）是一种顽强的侵略性神经内分泌型癌症，在过去的几十年中，对一线护理标准治疗的改变很小。与非小细胞肺癌（NSCLC）不同，SCLC几乎没有用于治疗干预的可行突变。赖氨酸特异性组蛋白脱甲基酶1A（LSD1也称为KDM1A）抑制剂先前已显示在SCLC模型中具有选择性活性，但潜在的机制尚不清楚。在这里，我们发现暴露于选择性LSD1抑制剂ORY-1001激活了NOTCH途径，导致转录因子ASCL1的抑制和SCLC肿瘤发生的抑制。我们的分析表明LSD1绑定到NOTCH1基因座，从而抑制NOTCH1表达和下游信号传导。用LSD1抑制剂重新激活NOTCH信号可减少ASCL1和神经内分泌细胞谱系基因的表达。击倒研究证实了基于药理抑制剂的结果。在体内，SCLC患者异种移植（PDX）模型中对LSD1抑制的敏感性与相应的NOTCH途径激活和神经内分泌表型抑制的程度相关。在化学抗性PDX模型中，ORY-1001诱导的NOTCH活化发生了完全而持久的肿瘤消退。我们的发现揭示了LSD1抑制剂如何在这种肿瘤中发挥作用，并支持其作为SCLC新型靶向疗法的潜力。在SCLC患者来源的异种移植（PDX）模型中对LSD1抑制的敏感性与随后的NOTCH途径激活和神经内分泌表型抑制的程度有关。在化学抗性PDX模型中，由ORY-1001诱导的NOTCH活化发生了完全而持久的肿瘤消退。我们的发现揭示了LSD1抑制剂如何在这种肿瘤中发挥作用，并支持其作为SCLC新型靶向疗法的潜力。在SCLC患者来源的异种移植（PDX）模型中对LSD1抑制的敏感性与随后的NOTCH途径激活和神经内分泌表型抑制的程度有关。在化学抗性PDX模型中，ORY-1001诱导的NOTCH活化发生了完全而持久的肿瘤消退。我们的发现揭示了LSD1抑制剂如何在这种肿瘤中发挥作用，并支持其作为SCLC新型靶向疗法的潜力。