Small-Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC-A and SCLC-N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E-box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes, such as BCL2, INSM1, MYC, and AURKA, which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles's heel, and how this is effectively exploited by lurbinectedin as a novel SCLC therapeutic endeavor.

中文翻译：

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ASCL1 和 NEUROD1 依赖性基因的启动子是 SCLC 细胞中 lurbinectedin 的特异性靶标。

小细胞肺癌（SCLC）是一种侵袭性神经内分泌恶性肿瘤，预后较差。在这里，我们专注于神经内分泌 SCLC 亚型 SCLC-A 和 SCLC-N，其转录成瘾由 ASCL1 和 NEUROD1 转录因子驱动，这些转录因子靶向 E-box 基序以激活高达 40% 的总基因，其启动子是根据 ATAC 和 H3K27Ac 特征，维持在稳定开放的染色质环境中。海洋代理 lurbinectedin 使用了这种杠杆作用，它优先针对位于转录起始位点下游的 CpG 岛，从而阻止 RNAPII 的延长并促进其降解。这消除了 ASCL1 和 NEUROD1 及其依赖基因（如 BCL2、INSM1、MYC 和 AURKA）的表达，它们负责相关的 SCLC 致瘤特性，例如抑制细胞凋亡和细胞存活，以及其部分神经内分泌特征。总之，我们展示了这些细胞的转录成瘾如何成为他们的致命弱点，以及 lurbinectedin 如何有效地利用这一点作为一种新的 SCLC 治疗尝试。