Characterizing ASCL1-Dependent Neuroendocrine Non-Small Cell Lung Cancers




Augustyn, Alexander

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In order to achieve personalized medicine for the treatment of lung cancer, it is important to accurately classify tumors using a combination of factors, including patho-physiological features, tumor gene expression profiles, response to therapy, and oncogene/tumor suppressor mutation status. Gene expression analyses, including immunohistochemistry, single mRNA transcript analyses, and genome-wide mRNA expression profiling, performed over the course of the last three decades suggest that distinct, poorly performing neuroendocrine tumors occur in about 10% of otherwise pathologically indistinguishable non-small cell lung cancers. A complete molecular characterization of these tumors is lacking because no pre-clinical model exists. Utilizing genome-wide mRNA expression profiling from lung cancer cell lines established from a variety of patients, it was discovered that a rare subgroup of non-small cell lung cancer (NSCLC) lines demonstrated similar gene expression compared to a known neuroendocrine tumor, small cell lung cancer (SCLC). Validation of transcript analysis verified this data, and demonstrated that a particular transcription factor, ASCL1, required during development for the formation of pulmonary neuroendocrine cells, is dramatically upregulated in the subgroup of non-small cell lung cancer with neuroendocrine features (NE-NSCLC). Other cancer models have demonstrated addiction of tumors to developmental transcription factors and termed these genes “lineage oncogenes.” By showing that NE-NSCLC cell lines are addicted to ASCL1 expression and function, it was established that ASCL1 is also a lineage oncogene. Transcription factors of the basic helix-loop-helix category are historically difficult to target with small molecules, so a downstream target analysis was performed in order to understand the ASCL1 transcriptome. ChIP-Seq analysis demonstrated that ASCL1 regulates many genes, including several that are inherently druggable. Further studies proved that ASCL1 directly regulates the transcription of the anti-apoptotic regulator BCL2. Inhibition of BCL2 in vitro and in vivo led to induction of apoptosis and tumor xenograft regression suggesting that BCL2 is a potential therapeutic target in ASCL1-dependent NE-NSCLCs. Analysis of the upstream regulation of ASCL1 showed that it depends on a paradoxical activation of the RAS/RAF/MEK/ERK pathway. Small molecule agonists of this pathway were utilized to demonstrate reduction of ASCL1 levels and induction of apoptosis. The combination of ERK activation with BCL2 inhibition was then shown to be a viable therapeutic strategy for ASCL1-dependent tumors in vitro.

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