He Min, Liu Shanshan, Gallolu Kankanamalage Sachith, Borromeo Mark D, Girard Luc, Gazdar Adi F, Minna John D, Johnson Jane E, Cobb Melanie H
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
Transl Oncol. 2018 Apr;11(2):292-299. doi: 10.1016/j.tranon.2018.01.004. Epub 2018 Feb 2.
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，被美国国立癌症研究所指定为难治性癌症，迫切需要新的合理治疗靶点。先前的研究已经确定，碱性螺旋-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的存活和进展至关重要，这些细胞包括SCLC和一部分非SCLC。以前，为了了解ASCL1如何在肺神经内分泌癌中启动肿瘤发生并确定ASCL1的转录靶点，我们对一系列肺癌细胞系进行了全基因组RNA测序分析，并结合了染色质免疫沉淀测序。通过该分析，我们发现编码上皮钠通道（αENaC）α亚基的基因SCNN1A与SCLC中的ASCL1表达高度相关。SCNN1A基因的产物ENaC可以用氨氯地平进行药理学抑制，氨氯地平是一种已临床使用近50年的药物。在体外，氨氯地平对依赖ASCL1的SCLC的生长抑制作用比对不依赖ASCL1的SCLC更强，并且减缓了异种移植中ASCL1驱动的SCLC的生长。我们得出结论，SCNN1A/αENaC是神经内分泌肺癌谱系癌基因ASCL1的直接转录靶点，可以通过药理学靶向产生抗肿瘤作用。
