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.