Abstract
The future of cancer therapy relies on identifying certain patient populations that will respond to one treatment but not another based on the properties of the tumor and additionally creating specific drugs that target genetic pathways required for a particular tumor's formation, growth, and maintenance. We have developed a pre-clinical model for a genetically identifiable clade of non-small cell lung cancer that exhibits neuroendocrine features. We utilized whole-genome mRNA expression array data from 119 NSCLC cell lines to identify a class of NSCLC lines that fit the neuroendocrine phenotype (NE-NSCLC). We identified 11 NSCLC cell lines (9.2%) that display a distinct neuroendocrine gene signature. A gene expressed in all putative NE-NSCLC cell lines is the potent neural-specific transcription factor ASCL1. We hypothesize that ASCL1 acts as a “lineage dependent oncogene” for NE-NSCLC and that associated with ASCL1's function in the molecular pathogenesis of these lung cancers will be a gene expression profile that contributes to the malignant phenotype, which will provide insight towards therapeutic targeting of this subset of NSCLC. In this regard, ASCL1 ChIP-Seq data combined with genome wide mRNA expression data identified a subset of genes whose expression appears to be regulated by ASCL1. In NSCLC patient populations, tumors expressing ASCL1 and the neuroendocrine gene signature demonstrated impaired prognosis compared to the other NSCLCs. Knockdown of ASCL1 in representative NSCLC cell lines reduced target gene expression, caused significant cell cycle defects, and induced marked apoptosis. NSCLC cell lines expressing ASCL1 demonstrate a cancer stem cell marker phenotype similar to that of small cell lung cancer, providing clues to the pathogenesis of the NE-NSCLC disease subset. Our results suggest that neuroendocrine gene expression in NSCLC is of clinical relevance, that ASCL1 is required for survival of the NE-NSCLC disease subset, while the integrated ASCL1 ChIP-Seq and mRNA expression data provide a roadmap for systematically searching for therapeutic targets for this phenotype and their mechanistic role in a cancer stem cell (initiating cell) subpopulation within these tumors.
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