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

Nature Medicine volume 21, pages 1163–1171 (2015)Cite this article

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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.

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Figure 1: BET protein inhibition suppresses PDAC growth and improves survival in a PDAC mouse model.
Figure 2: MYC and inflammation are key tumorigenic drivers of PDAC that are inhibited by JQ1 treatment and BET protein inhibition.
Figure 3: Synergistic inhibitory effects of JQ1 and the HDAC inhibitor SAHA in PDAC.
Figure 4: Combined treatment with JQ1 and SAHA inhibits PDAC progression in vivo.
Figure 5: JQ1 and SAHA synergistically suppress lung adenocarcinoma growth in vivo.
Figure 6: Identification of p57 as a key mediator of PDAC sensitivity to JQ1 and SAHA co-treatment using a gene editing platform in the pancreas of mice.

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Acknowledgements

P.K.M. and A.H. significantly contributed to the work and are listed as co-first authors based on a previous agreement. We thank C. Vakoc (Cold Spring Harbor Laboratory) for sharing shRNA plasmids, M. Winslow (Stanford University) for the R26CAG-tdTomato reporter mice and I. Moreno de Alboran (Spanish National Biotechnology Centre) for MycloxP mice. This work was supported by the German Research Foundation (SFB824/C4 to J.T.S.), the European Union's Seventh Framework Program for research, technological development and demonstration (FP7/CAM-PaC) under grant agreement 602783, the German Cancer Consortium (DKTK) (to R.M.S. and J.T.S.), and the Lustgarten Foundation (J.S.). P.K.M. was supported by the Tobacco-Related Disease Research Program, a Dean's Fellowship from Stanford University, and the Child Health Research Institute and Lucile Packard Foundation for Children's Health at Stanford. J.S. is the Harriet and Mary Zelencik Scientist in Children's Cancer and Blood Diseases. T.K. was supported by a Boehringer Ingelheim Fonds MD Fellowship.

Author information

Author notes

  1. Mert Erkan

    Present address: Current address: Department of Surgery, Koc University School of Medicine, Istanbul, Turkey.,

  2. Irene Esposito

    Present address: Current address: Institute of Pathology, Heinrich-Heine University, Düsseldorf, Germany.,

  3. Jens T Siveke

    Present address: Current address: Division of Translational Solid Tumor Oncology, German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany.,

  4. Pawel K Mazur and Alexander Herner: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Stanford University School of Medicine, California, USA

    Pawel K Mazur, Timo Kuschma, Leanne C Sayles, E Alejandro Sweet-Cordero & Julien Sage

  2. Department of Genetics, Stanford University School of Medicine, California, USA

    Pawel K Mazur, Stephano S Mello, Timo Kuschma, Laura D Attardi & Julien Sage

  3. Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Alexander Herner, Matthias Wirth, Marija Trajkovic-Arsic, Aayush Gupta, Roland M Schmid, Guenter Schneider & Jens T Siveke

  4. Department of Radiation Oncology, Stanford University School of Medicine, California, USA

    Stephano S Mello & Laura D Attardi

  5. Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Simone Hausmann, Mert Erkan & Jörg Kleeff

  6. Department of Biology, David H. Koch Institute for Integrative Cancer Research, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Francisco J Sánchez-Rivera & Tyler Jacks

  7. Department of Medicine, Stanford University School of Medicine, California, USA

    Shane M Lofgren & Purvesh Khatri

  8. Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA

    Shane M Lofgren & Purvesh Khatri

  9. Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany

    Stephan A Hahn

  10. Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany

    Deepak Vangala

  11. Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Irina Heid, Peter B Noël & Rickmer Braren

  12. Institute of Pathology, University of Tübingen, Tübingen, Germany

    Bence Sipos

  13. Institute of Virology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Mathias Heikenwalder

  14. Division of Chronic Inflammation and Cancer, German Cancer Research center (DKFZ), Heidelberg, Germany

    Mathias Heikenwalder

  15. Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany

    Elisabeth Heßmann & Volker Ellenrieder

  16. Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Irene Esposito

  17. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    James E Bradner

  18. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Roland M Schmid & Jens T Siveke

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  1. Pawel K Mazur
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Contributions

P.K.M. conceived the study; designed and performed the in vivo studies of pancreatitis-induced PDAC and the Myc knockout studies, and established and performed the five-arm patient-derived PDAC xenograft assays; performed the drug screen, the tissue organoids experiments, the cell culture studies, the ChIP analysis, and the target validation assays in cell lines and in vivo; designed and performed survival treatment of mouse models of PDAC and LAC; designed and performed in vivo CRISPR-Cas9 studies; and coordinated the project, interpreted data, and drafted the manuscript. A.H. performed survival treatment of the Kras;p53 mouse model of PDAC, contributed to MRI animal imaging and tumor volume analysis, contributed to analysis of PDAC xenografts and Myc knockout studies, generated mouse expression arrays, and contributed to cell culture studies and interpretation of the data. S.S.M. and L.D.A. contributed to design and testing of intrapancreatic viral injections. M.W. and G.S. contributed to cell culture studies and interpretation of data. S.H., M.E. and J.K. obtained and prepared surgical tissue samples of PDAC for xenograft and tissue studies. M.T.-A., A.G., R.B., I.H. and P.B.N. performed MRI animal imaging and interpretation and tumor volume analysis. S.M.L. and P.K. performed bioinformatics analyses. S.A.H. and D.V. established and performed treatment of the two-arm PDAC xenograft study and generated human expression arrays. F.J.S.-R. and T.J. designed and constructed pSECC lentivirus. B.S. and I.E., pathologists, performed histological and IHC tissue evaluation and lesion progression quantification. M.H. contributed to IHC analysis. E.H. and V.E. contributed to data interpretation. T.K. contributed to plasmid and lentivirus preparation. L.C.S. and E.A.S.-C. obtained surgical tissue samples of LAC and developed PDX models. J.E.B. contributed to JQ1 inhibitor study protocols and interpretation of data. R.M.S. performed data interpretation. J.S. and J.T.S were equally responsible for supervision of research, data interpretation and manuscript preparation.

Corresponding authors

Correspondence to Pawel K Mazur, Julien Sage or Jens T Siveke.

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The authors declare no competing financial interests.

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Mazur, P., Herner, A., Mello, S. et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med 21, 1163–1171 (2015). https://doi.org/10.1038/nm.3952

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