摘要：SummaryLineage-defining transcription factors (LTFs) play key roles in small-cell lung cancer (SCLC) pathophysiology. Delineating the LTF-regulated genes operative in SCLC could provide a road map to identify SCLC dependencies. We integrated chromatin landscape and transcriptome analyses of patient-derived SCLC preclinical models to identify super-enhancers (SEs) and their associated genes in the ASCL1-, NEUROD1-, and POU2F3-high SCLC subtypes. We find SE signatures predict LTF-based classification of SCLC, and the SE-associated genes are enriched with those defined as common essential genes in DepMap. In addition, in ASCL1-high SCLC, we show ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in NOTCH signaling, catecholamine biosynthesis, and cell-cycle processes. Depletion of ASCL1 demonstrates it is a key dependency factor in preclinical SCLC models and directly regulates multiple DepMap-defined essential genes. We provide LTF/SE-based subtype-specific gene sets for SCLC for further therapeutic investigation.Graphical abstractDisplay OmittedHighlights•Super-enhancers support lineage-defining transcription factor SCLC classification•SCLC super-enhancer-associated genes represent essential and lineage-identity genes•ASCL1, NKX2-1, and PROX1 proteins interact in a complex in SCLC-A•ASCL1, NKX2-1, and PROX1 regulate Notch-signaling, NE-specific, and cell-cycle genesMolecular biology; Bioinformatics; Cancer systems biology
