Neuroendocrine specific lung cancers comprise about 10% of non-small cell lung cancer (NSCLC) cases and all small cell lung cancer (SCLC) cases. Studies have previously shown that the transcription factor achaete-scute homolog 1 (ASCL1) is a cancer “lineage” factor required for the development and survival of SCLC, and is highly expressed in neuroendocrine-specific NSCLC (NE-NSCLC). CTD2 researchers from UT Southwestern Medical Center discovered that ASCL1 is required for survival of NE-NSCLC cells, which may lead to discoveries of new therapeutic vulnerabilities for this cancer.
To identify new therapeutic targets, the researchers used ChIP-seq and gene expression analysis to identify 72 genes that are differentially expressed in ASCL1 producing cells. One of these genes, anti-apoptotic factor B-cell CLL/lymphoma 2 (BCL2), was previously shown to be an effective drug target for SCLC. The researchers found ABT-263, a Bcl-2 small molecule inhibitor, caused cell death of NE-SCLC cells in tissue culture experiments and reduced tumor size in a mouse xenograft model. The sensitivity of NE-NSCLC and SCLC to Bcl-2 small molecule inhibitors suggests ASCL1 activated genes may be promising therapeutic targets for treating neuroendocrine lung cancers.