Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma, designated as a recalcitrant cancer by the National Cancer Institute, in urgent need of new rational therapeutic targets. Previous studies have determined that the basic helix-loop-helix transcription factor achaete-scute homolog 1 (ASCL1) is essential for the survival and progression of a fraction of pulmonary neuroendocrine cancer cells, which include both SCLC and a subset of non-SCLC. Previously, to understand how ASCL1 initiates tumorigenesis in pulmonary neuroendocrine cancer and identify the transcriptional targets of ASCL1, whole-genome RNA-sequencing analysis combined with chromatin immunoprecipitation-sequencing was performed with a series of lung cancer cell lines. From this analysis, we discovered that the gene SCNN1A, which encodes the alpha subunit of the epithelial sodium channel (αENaC), is highly correlated with ASCL1 expression in SCLC. The product of the SCNN1A gene ENaC can be pharmacologically inhibited with amiloride, a drug that has been used clinically for close to 50 years. Amiloride inhibited growth of ASCL1-dependent SCLC more strongly than ASCL1-independent SCLC in vitro and slowed growth of ASCL1-driven SCLC in xenografts. We conclude that SCNN1A/αENaC is a direct transcriptional target of the neuroendocrine lung cancer lineage oncogene ASCL1 that can be pharmacologically targeted with antitumor effects.

小细胞肺癌（SCLC）是一种侵袭性神经内分泌癌，被美国国家癌症研究所（National Cancer Institute）指定为顽固性癌症，迫切需要新的合理治疗靶点。先前的研究已经确定，基本的螺旋-环-螺旋转录因子achaete-scute同源物1（ASCL1）对于一部分肺神经内分泌癌细胞（包括SCLC和非SCLC的一部分）的存活和进展至关重要。以前，为了了解ASCL1如何启动肺神经内分泌癌的肿瘤发生并确定ASCL1的转录靶标，对一系列肺癌细胞株进行了全基因组RNA测序分析和染色质免疫沉淀测序分析。通过此分析，我们发现了基因SCNN1A，它编码上皮钠通道的α亚基（αENaC），与SCLC中ASCL1的表达高度相关。SCNN1A基因ENaC的产物可以被amiloride抑制，这在临床上已经使用了近50年。阿米洛利比不依赖ASCL1的SCLC更强烈地抑制ASCL1依赖的SCLC的生长异种移植中体外生长和减慢ASCL1驱动的SCLC的生长。我们得出的结论是，SCNN1A /αENaC是神经内分泌肺癌谱系癌基因ASCL1的直接转录靶标，可以通过药理学针对其抗肿瘤作用。