Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC. ATACseq and RNAseq experiments were performed in SCLC cells after pharmacological inhibition of SMARCA4. DNA binding of SMARCA4 was characterized by ChIPseq in high-NE SCLC patient derived xenografts (PDXs). Enrichment analyses were applied to transcriptomic data. Combination of FHD-286 and afatinib was tested in vitro and in a set of chemo-resistant SCLC PDXs in vivo. SMARCA4 expression positively correlates with that of NE genes in both SCLC cell lines and patient tumors. Pharmacological inhibition of SMARCA4 with FHD-286 induces the loss of NE features and downregulates neuroendocrine and neuronal signaling pathways while activating non-NE factors. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, enhancing NE programs. Enrichment analysis applied to high-confidence SMARCA4 targets confirmed neuron related pathways as the top GO Biological processes regulated by SMARCA4 in SCLC. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST transcript splicing. Furthermore, SMARCA4 inhibition drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib. This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC.

中文翻译：

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SMARCA4 通过调节神经内分泌转录因子和 REST 剪接来控制小细胞肺癌的状态可塑性


小细胞肺癌 （SCLC） 可分为具有不同神经内分泌 （NE） 分化程度的转录亚型。最近的证据支持亚型之间的可塑性，偏向于在疾病进展或获得性化疗耐药时采用低 NE 状态。在这里，我们确定了 SMARCA4（SWI/SNF 复合物的催化亚基）作为 SCLC 亚型转移调节因子的作用。在 SMARCA4 药物抑制后的 SCLC 细胞中进行 ATACseq 和 RNAseq 实验。在高 NE SCLC 患者来源的异种移植物 （PDX） 中通过 ChIPseq 表征 SMARCA4 的 DNA 结合。对转录组数据进行富集分析。FHD-286 和阿法替尼的组合在体外和一组化疗耐药 SCLC PDX 体内进行了测试。SMARCA4表达与 SCLC 细胞系和患者肿瘤中 NE 基因的表达呈正相关。FHD-286 对 SMARCA4 的药理学抑制诱导 NE 特征的丧失，并下调神经内分泌和神经元信号通路，同时激活非 NE 因子。SMARCA4 与编码 NE 系转录因子 ASCL1 和 NEUROD1 的基因位点结合，并改变染色质的可及性，增强 NE 程序。应用于高置信度 SMARCA4 靶标的富集分析证实，神经元相关通路是 SCLC 中受 SMARCA4 调节的首要 GO 生物过程。同时，SMARCA4 还通过调节 SRRM4 依赖性 REST 转录本剪接来控制 REST，一种已知的 NE 表型抑制因子。此外，SMARCA4抑制驱动 SCLC 中的 ERBB 通路激活，使 SCLC 肿瘤对阿法替尼敏感。本研究将 SMARCA4 指定为 NE 状态可塑性的关键调节因子，并确定了 SCLC 的新型治疗策略。