title: Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms.
abstract: Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Xiarong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Valia T
authors.initials: VT
authors.lastname: Mihaylova
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Leena
authors.initials: L
authors.lastname: Kuruvilla
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Stephen
authors.initials: S
authors.lastname: Viviano
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Baldassarre
authors.affiliation: Gilead Sciences, Foster City, CA 94404;
authors.forename: David
authors.initials: D
authors.lastname: Sperandio
authors.affiliation: Gilead Sciences, Foster City, CA 94404;
authors.forename: Ruben
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Gilead Sciences, Foster City, CA 94404;
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.affiliation: Gilead Sciences, Foster City, CA 94404;
authors.forename: Jamie G
authors.initials: JG
authors.lastname: Bates
authors.affiliation: Gilead Sciences, Foster City, CA 94404;
authors.forename: David G
authors.initials: DG
authors.lastname: Breckenridge
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; joseph.schlessinger@yale.edu ben.turk@yale.edu david.calderwood@yale.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; joseph.schlessinger@yale.edu ben.turk@yale.edu david.calderwood@yale.edu.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520 joseph.schlessinger@yale.edu ben.turk@yale.edu david.calderwood@yale.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
mesh_terms: D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004351:Drug Resistance / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014230:Triazoles; C561695:(+)-JQ1 compound; C511956:TRIM33 protein, human; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins
keywords: JQ1; TGF-β; TRIM33; bromodomain inhibitor; drug resistance