Predictive biomarker of BET bromodomain inhibitor in Small cell lung cancer

Division Of Basic Sciences - Nci

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Abstract

We hypothesized that BET bromodomain proteins are essential for the function of master transcription factors in SCLC and blocking these proteins could provide an alternative approach to target these master transcription factors. We have identified 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. Blocking BET bromodomain proteins by inhibitors led to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, resulting in 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 sensitivity in SCLC. Altogether, our study reveals an essential role of BET bromodomain proteins in regulating NEUROD1 transactivation and could be a target to block the master transcription factors in SCLC.