Data from Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of <i>ASCL1</i> Gene Expression

Abstract

<div>Abstract<p>The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of <i>MYC</i> and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in <i>MYC</i>-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 downregulation of the lineage-specific transcription factor <i>ASCL1</i>. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the <i>ASCL1</i> enhancer, and the ability of JQ1 to disrupt the interaction. The importance of <i>ASCL1</i> as a potential driver oncogene in SCLC is further underscored by the observation that <i>ASCL1</i> is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (<i>MYC</i>, <i>MYCN</i>, and <i>SOX2</i>) 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. <i>Mol Cancer Ther; 14(10); 2167–74. ©2015 AACR</i>.</p></div>