GSE210110
BET Inhibitors Target the SCLC-N subtype of Small Cell Lung Cancer by Blocking NEUROD1 Transactivation
Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as its transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. To investigate what genes are affected by NHWD-870 (a BET inhibitor) in SCLC-N subtype tumors in vivo, we performed an RNA-seq analysis of the tumor cells isolated from the LX22 PDX after NHWD-870 treatment at 2mg/kg via oral gavage daily for five days. Overall design: Each group (NHWD870 vs. vehicle) contained six tumors.