Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression.

Ryan Lenhart,Tai Wong,Ashok Purandare,Liang Schweizer,Susan Wee,Ming Lei,Heshani Desilva,Kathy Johnston,Petra Ross-Macdonald,Russell Peterson,Stefan Kirov,Jian Cao,Craig Fairchild

doi:10.1158/1535-7163.mct-15-0037

Ryan Lenhart, Tai Wong + Show 11 more

Open Access

https://doi.org/10.1158/1535-7163.mct-15-0037

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Abstract

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 MYC and other genes that are important to disease pathology. Pharmacologic 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 downregulation of the lineage-specific transcription factor ASCL1. 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 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 overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and 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.

Highlights

Bromodomains are protein interaction modules that recognize acetylation motifs commonly found on the unstructured tails of histones [1]
The binding of BET proteins to acetylated histones allows the recruitment of chromatin regulators, such as transcription factors and nucleosome remodeling complexes, to specific chromatin sites resulting in targeted gene expression
Through gene-expression profiling analyses, we identified achaete-scute homolog-1 (ASCL1) to be a BET target gene expressed in BET-sensitive small cell lung cancer (SCLC)

Summary

Introduction

Bromodomains are protein interaction modules that recognize acetylation motifs commonly found on the unstructured tails of histones [1]. There has been increasing interest in the BET family proteins fueled by the discovery of selective and potent small-molecule inhibitors that compete with acetylated histones in binding to BET family bromodomains. JQ1 and other BET inhibitors have been found to inhibit the proliferation of cancer cell lines representing an array of tumor histologies [7, 12,13,14,15] From these studies, it is clear that BET inhibitors have therapeutic utility well beyond hematologic diseases. We show that JQ1 inhibits the growth of SCLC cells by downregulating ASCL1 gene expression This observation parallels the growth effects observed with JQ1 in multiple myeloma where in place of www.aacrjournals.org. MYC the downregulation of ASCL1 expression underlies JQ1 sensitivity in SCLC

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Disclosure of Potential Conflicts of Interest