title: Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression.
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.
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lenhart
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kirov
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Heshani
authors.initials: H
authors.lastname: Desilva
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Kathy
authors.initials: K
authors.lastname: Johnston
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Russell
authors.initials: R
authors.lastname: Peterson
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Liang
authors.initials: L
authors.lastname: Schweizer
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Ashok
authors.initials: A
authors.lastname: Purandare
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Petra
authors.initials: P
authors.lastname: Ross-Macdonald
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Craig
authors.initials: C
authors.lastname: Fairchild
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Tai
authors.initials: T
authors.lastname: Wong
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey. susan.wee@bms.com.
authors.forename: Susan
authors.initials: S
authors.lastname: Wee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C065500:ASCL1 protein, human; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins