title: The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models.
abstract: The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Garcia
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Miller
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Kreitzburg
authors.affiliation: Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Council
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Gamblin
authors.affiliation: Division of General Surgery, Gastrointestinal Surgery or Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Christein
authors.affiliation: Division of General Surgery, Gastrointestinal Surgery or Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Heslin
authors.affiliation: Division of General Surgery, Gastrointestinal Surgery or Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Arnoletti
authors.affiliation: Division of General Surgery, Gastrointestinal Surgery or Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Richardson
authors.affiliation: Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.affiliation: Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Hanna
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Cramer
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Qi
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; C486765:Dner protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D014230:Triazoles