BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation

Small-cell lung cancer (SCLC) is a recalcitrant malignancy that (ASCL1, NEUROD1, POU2F3, and YAP1) have been identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. However, these master transcription factors have not been found directly druggable. We hypothesized that blocking their transcriptional coactivator(s) could provide an alternative approach to target these master transcription factors. Here, we identify that BET proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIPseq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET proteins in the SCLC genome. Blocking BET proteins by inhibitors led to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, resulting in the inhibition of 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 sen-sitivity in SCLC. Altogether, our study reveals that BET proteins are essential in regulating NEUROD1 transactivation and are promis-ing targets in SCLC-N subtype tumors.

Automated summary

Small-cell lung cancer (SCLC) is a difficult-to-treat malignancy. BET proteins have been found to interact with NEUROD1 and function as transcriptional coactivators in SCLC. Blocking BET proteins with inhibitors suppresses NEUROD1-target genes, inhibiting SCLC growth in vitro and in vivo. LSAMP, a membrane protein, is identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. These findings highlight the essential role of BET proteins and their potential as targets in SCLC-N subtype tumors.