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Nat Med. 2015 Oct;21(10):1163-71. doi: 10.1038/nm.3952. Epub 2015 Sep 21.

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

Author information

1
Department of Pediatrics, Stanford University School of Medicine, California, USA.
2
Department of Genetics, Stanford University School of Medicine, California, USA.
3
Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
4
Department of Radiation Oncology, Stanford University School of Medicine, California, USA.
5
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
6
David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
7
Department of Medicine, Stanford University School of Medicine, California, USA.
8
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA.
9
Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.
10
Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany.
11
Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
12
Institute of Pathology, University of Tübingen, Tübingen, Germany.
13
Institute of Virology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
14
Division of Chronic Inflammation and Cancer, German Cancer Research center (DKFZ) Heidelberg, Germany.
15
Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
16
Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
17
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
18
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

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.

PMID:
26390243
PMCID:
PMC4959788
DOI:
10.1038/nm.3952
[Indexed for MEDLINE]
Free PMC Article

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