Sensitivity of SCLC to BET inhibition is mediated by regulation of ASCL1 gene expression 1 Sensitivity of Small-Cell Lung Cancer to BET Inhibition is Mediated by Regulation of ASCL1 Gene Expression

Running Title: ASCL1 is a target gene of the BET inhibitor JQ1 in SCLC Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: The BET (bromondomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematological cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacological inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers such as multiple myeloma. In this study we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in down-regulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNA interference. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is over-expressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition, and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.