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PMID: 26390243 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.

Nature medicine ·Vol. 21 ·No. 10 ·2015-10-00 ·Pages 1163-71

Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Heßmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT

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.

MeSH Terms
Adenocarcinoma/drug therapy,therapy Animals Carcinoma, Pancreatic Ductal/drug therapy,therapy Clustered Regularly Interspaced Short Palindromic Repeats Epigenesis, Genetic Histone Deacetylase Inhibitors/therapeutic use Humans Mice Proteins/antagonists & inhibitors
Chemicals
Histone Deacetylase Inhibitors Proteins
Authors & Affiliations
32 authors, click to expand affiliations / ORCID
Mazur Pawel K
Department of Pediatrics, Stanford University School of Medicine, California, USA. | Department of Genetics, Stanford University School of Medicine, California, USA.
Herner Alexander
Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Mello Stephano S
Department of Genetics, Stanford University School of Medicine, California, USA. | Department of Radiation Oncology, Stanford University School of Medicine, California, USA.
Wirth Matthias
Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Hausmann Simone
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Sánchez-Rivera Francisco J
David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Lofgren Shane M
Department of Medicine, Stanford University School of Medicine, California, USA. | Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA.
Kuschma Timo
Department of Pediatrics, Stanford University School of Medicine, California, USA. | Department of Genetics, Stanford University School of Medicine, California, USA.
Hahn Stephan A
Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.
Vangala Deepak
Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany.
Trajkovic-Arsic Marija
Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Gupta Aayush
Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Heid Irina
Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Noël Peter B
Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Braren Rickmer
Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Erkan Mert ORCID
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Kleeff Jörg ORCID
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Sipos Bence ORCID
Institute of Pathology, University of Tübingen, Tübingen, Germany.
Sayles Leanne C
Department of Pediatrics, Stanford University School of Medicine, California, USA.
Heikenwalder Mathias
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.
Heßmann Elisabeth
Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
Ellenrieder Volker
Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
Esposito Irene
Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Jacks Tyler
David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Bradner James E
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Khatri Purvesh
Department of Medicine, Stanford University School of Medicine, California, USA. | Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA.
Sweet-Cordero E Alejandro
Department of Pediatrics, Stanford University School of Medicine, California, USA.
Attardi Laura D
Department of Genetics, Stanford University School of Medicine, California, USA. | Department of Radiation Oncology, Stanford University School of Medicine, California, USA.
Schmid Roland M
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.
Schneider Guenter
Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Sage Julien
Department of Pediatrics, Stanford University School of Medicine, California, USA. | Department of Genetics, Stanford University School of Medicine, California, USA.
Siveke Jens T
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.
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.3952
Published
2015-10-00
Epub
2015-00-21
Pages
1163-71
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC4959788
Subset
IM
Grants
NCI NIH HHS · K99 CA197816 · United States
NCI NIH HHS · R00 CA197816 · United States
NIAID NIH HHS · U19 AI109662 · United States
Databases
PDB
GSE64836, GSE64837
Corrections
CommentIn
PMID: 26441249
External Links
PubMed source DOI: 10.1038/nm.3952 PMC Full Text View journal details
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