小细胞肺癌(SCLC)迅速抵抗细胞毒化疗和免疫检查点抑制剂(ICI)治疗。因此，需要新的不交叉抗药治疗方法。SCLC细胞致力于神经内分泌线性发育然后发育停滞。我们发现DNA甲基转移酶1(DNMT1)参与了这种发育停滞。具体而言，我们发现：(1)在被抑制的神经内分泌基因上，DNMT1写入的甲基化CpG抑制标记保留，即使其他抑制标记被清除；(2)DNMT1经常增加，而对DNMT1具有功能对抗作用的Ten-Eleven-Translocation 2(TET2)被删除；(3)DNMT1被招募到SCLC细胞的神经内分泌主转录因子(ASCL1、NEUROD1)中枢；(4)DNMT1敲低激活ASCL1目标基因，并通过终末分化途径释放SCLC细胞的周期退出，这种周期退出不需要细胞毒化疗所使用的p53凋亡途径。因此，使用临床化合物抑制DNMT1/共抑制剂可以延长具有化疗耐受和ICI耐受、p53缺失的广泛扩散SCLC小鼠的生存时间。因此，可以利用SCLC细胞的谱系承诺进行非细胞毒疗法的治疗，以治疗化疗/ICI耐药的SCLC。 © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells are committed into neuroendocrine lineage then maturation arrested. Implicating DNA methyltransferase 1 (DNMT1) in the maturation arrests, we find (1) the repression mark methylated CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other repression marks are erased; (2) DNMT1 is recurrently amplified, whereas Ten-Eleven-Translocation 2 (TET2), which functionally opposes DNMT1, is deleted; (3) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (4) DNMT1 knockdown activated ASCL1-target genes and released SCLC cell-cycling exits by terminal lineage maturation, which are cycling exits that do not require the p53/apoptosis pathway used by cytotoxic chemotherapy. Inhibiting DNMT1/corepressors with clinical compounds accordingly extended survival of mice with chemorefractory and ICI-refractory, p53-null, disseminated SCLC. Lineage commitment of SCLC cells can hence be leveraged into non-cytotoxic therapy able to treat chemo/ICI-refractory SCLC.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.