小细胞肺癌（SCLC）是一种神经内分泌（NE）来源的顽固性癌症。几十年来，小细胞肺癌的治疗方法一直缺乏变化。在这里，我们使用临床前模型来识别 SCLC 的新治疗漏洞，该漏洞由可靶向的 Jumonji 赖氨酸脱甲基酶 (KDM) 家族组成。我们发现 Jumonji 去甲基酶抑制剂可阻止恶性生长，并且依托泊苷耐药的 SCLC 细胞系对 Jumonji 抑制特别敏感。从机制上讲，小分子介导的 Jumonji KDM 抑制会激活内质网 (ER) 应激基因，上调 ER 应激信号传导，并引发细胞凋亡。此外，Jumonji 抑制剂可降低 SCLC NE 标记 INSM1 和 Secretogranin-3 以及驱动转录因子 ASCL1 和 NEUROD1 的蛋白水平。 KDM4A 是一种在 SCLC 中高表达的 Jumonji 去甲基化酶，也是一种已知的 ER 应激基因调节因子，KDM4A 的基因敲除可诱导 ER 应激反应基因，减少 INSM1、Secretogranin-3 和 NEUROD1，并在体外和体内抑制 SCLC 的增殖。最后，我们证明两种不同的小分子 Jumonji KDM 抑制剂（泛抑制剂 JIB-04 和 KDM4 抑制剂 SD70）可阻断体内 SCLC 肿瘤异种移植物的生长。我们的研究强调了 Jumonji KDM 抑制剂针对 SCLC 的转化潜力，根据最近开展的评估此类药物的临床试验，这是一种临床上可行的方法，并将 KDM4A 确立为跨 SCLC 亚型的相关靶标。© 2024。作者。

Small cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family. We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death. Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo. Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes.© 2024. The Author(s).