title: Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, California, USA.|Department of Genetics, Stanford University School of Medicine, California, USA.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Herner
authors.affiliation: Department of Genetics, Stanford University School of Medicine, California, USA.|Department of Radiation Oncology, Stanford University School of Medicine, California, USA.
authors.forename: Stephano S
authors.initials: SS
authors.lastname: Mello
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Hausmann
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sánchez-Rivera
authors.affiliation: Department of Medicine, Stanford University School of Medicine, California, USA.|Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA.
authors.forename: Shane M
authors.initials: SM
authors.lastname: Lofgren
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, California, USA.|Department of Genetics, Stanford University School of Medicine, California, USA.
authors.forename: Timo
authors.initials: T
authors.lastname: Kuschma
authors.affiliation: Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Hahn
authors.affiliation: Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany.
authors.forename: Deepak
authors.initials: D
authors.lastname: Vangala
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Marija
authors.initials: M
authors.lastname: Trajkovic-Arsic
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Aayush
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Heid
authors.affiliation: Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Noël
authors.affiliation: Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Rickmer
authors.initials: R
authors.lastname: Braren
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Mert
authors.identifier: http://orcid.org/0000-0002-2753-0234
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Jörg
authors.identifier: http://orcid.org/0000-0003-3432-6669
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Institute of Pathology, University of Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.identifier: http://orcid.org/0000-0002-7311-3343
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, California, USA.
authors.forename: Leanne C
authors.initials: LC
authors.lastname: Sayles
authors.affiliation: Institute of Virology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research center (DKFZ) Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Heßmann
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ellenrieder
authors.affiliation: Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Medicine, Stanford University School of Medicine, California, USA.|Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA.
authors.forename: Purvesh
authors.initials: P
authors.lastname: Khatri
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, California, USA.
authors.forename: E Alejandro
authors.initials: EA
authors.lastname: Sweet-Cordero
authors.affiliation: Department of Genetics, Stanford University School of Medicine, California, USA.|Department of Radiation Oncology, Stanford University School of Medicine, California, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Guenter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, California, USA.|Department of Genetics, Stanford University School of Medicine, California, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000628:therapy; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000628:therapy; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D011506:Proteins / Q000037:antagonists & inhibitors*
chemical_list: D056572:Histone Deacetylase Inhibitors; D011506:Proteins