Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).

    CAS  PubMed  Google Scholar 

  2. Hezel, A.F., Kimmelman, A.C., Stanger, B.Z., Bardeesy, N. & Depinho, R.A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Ghaneh, P., Costello, E. & Neoptolemos, J.P. Biology and management of pancreatic cancer. Gut 56, 1134–1152 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Maitra, A. & Hruban, R.H. Pancreatic cancer. Annu. Rev. Pathol. 3, 157–188 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ryan, D.P., Hong, T.S. & Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039–1049 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Collins, M.A. & Pasca di Magliano, M. Kras as a key oncogene and therapeutic target in pancreatic cancer. Frontiers Physiol. 4, 407 (2013).

    Google Scholar 

  7. Infante, J.R. et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur. J. Cancer 50, 2072–2081 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Bardeesy, N. & DePinho, R.A. Pancreatic cancer biology and genetics. Nat. Rev. Cancer 2, 897–909 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Biankin, A.V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bardeesy, N. et al. Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl. Acad. Sci. USA 103, 5947–5952 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hingorani, S.R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Hingorani, S.R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Gidekel Friedlander, S.Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Morton, J.P. et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl. Acad. Sci. USA 107, 246–251 (2010).

    Article  PubMed  Google Scholar 

  16. Bardeesy, N. et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cook, N., Jodrell, D.I. & Tuveson, D.A. Predictive in vivo animal models and translation to clinical trials. Drug Discov. Today 17, 253–260 (2012).

    Article  PubMed  Google Scholar 

  18. Witkiewicz, A.K. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6, 6744 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Baylin, S.B. & Jones, P.A. A decade of exploring the cancer epigenome—biological and translational implications. Nat. Rev. Cancer 11, 726–734 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McCleary-Wheeler, A.L. et al. Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett. 328, 212–221 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Delmore, J.E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Means, A.L. et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132, 3767–3776 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Morris, J.P., Cano, D.A., Selkine, S., Wang, S.C. & Hebrok, M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sahai, V. et al. BET bromodomain inhibitors block growth of pancreatic cancer cells in three-dimensional collagen. Mol. Cancer Ther. 13, 1907–1917 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Von Hoff, D.D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sherman, M.H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ardito, C.M. et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Olive, K.P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Singh, M. et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat. Biotechnol. 28, 585–593 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Garcia, P.L. et al. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene doi:10.1038/onc.2015.126 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Roy, N. et al. Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation. Genes Dev. 29, 658–671 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schleger, C., Verbeke, C., Hildenbrand, R., Zentgraf, H. & Bleyl, U. c-MYC activation in primary and metastatic ductal adenocarcinoma of the pancreas: Incidence, mechanisms, and clinical significance. Mod. Pathol. 15, 462–469 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Fukuda, A. et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19, 441–455 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. McAllister, F. et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25, 621–637 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pylayeva-Gupta, Y., Lee, K.E., Hajdu, C.H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sodir, N.M. et al. Endogenous Myc maintains the tumor microenvironment. Genes Dev. 25, 907–916 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rielland, M. et al. Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression. J. Clin. Invest. 124, 2125–2135 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Corcoran, R.B. et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 71, 5020–5029 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Obata, J. et al. p48 subunit of mouse PTF1 binds to RBP-Jkappa/CBF-1, the intracellular mediator of Notch signalling, and is expressed in the neural tube of early stage embryos. Genes Cells 6, 345–360 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Aguirre, A.J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Feldser, D.M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572–575 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Adhikary, S. et al. Miz1 is required for early embryonic development during gastrulation. Mol. Cell. Biol. 23, 7648–7657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sato, N., Matsubayashi, H., Abe, T., Fukushima, N. & Goggins, M. Epigenetic down-regulation of CDKN1C/p57KIP2 in pancreatic ductal neoplasms identified by gene expression profiling. Clin. Cancer Res. 11, 4681–4688 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Yan, Y., Frisen, J., Lee, M.H., Massague, J. & Barbacid, M. Ablation of the CDK inhibitor p57(Kip2) results in increased apoptosis and delayed differentiation during mouse development. Genes Dev. 11, 973–983 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Vlachos, P., Nyman, U., Hajji, N. & Joseph, B. The cell cycle inhibitor p57(Kip2) promotes cell death via the mitochondrial apoptotic pathway. Cell Death Differ. 14, 1497–1507 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Sánchez-Rivera, F.J. et al. Rapid modelling of cooperating genetic events in cancer through somatic genome editing. Nature 516, 428–431 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhao, R.Y. et al. CDK inhibitor p57(Kip2) is downregulated by Akt during HER2-mediated tumorigenicity. Cell Cycle 12, 935–943 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Grasso, C.S. et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat. Med. 21, 555–559 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. De Raedt, T. et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514, 247–251 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Shimamura, T. et al. Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Clin. Cancer Res. 19, 6183–6192 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Kawaguchi, Y. et al. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genet. 32, 128–134 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29, 418–425 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. de Alboran, I.M. et al. Analysis of C-MYC function in normal cells via conditional gene-targeted mutation. Immunity 14, 45–55 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Mazur, P.K. et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510, 283–287 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Matzuk, M.M. et al. Small-molecule inhibition of BRDT for male contraception. Cell 150, 673–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hruban, R.H. et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res. 66, 95–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Jameson, K.L. et al. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nat. Med. 19, 626–630 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hsu, P.D. et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat. Biotechnol. 31, 827–832 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ran, F.A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tiscornia, G., Singer, O. & Verma, I.M. Production and purification of lentiviral vectors. Nat. Protoc. 1, 241–245 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Kim, M.P. et al. Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat. Protoc. 4, 1670–1680 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. José, A. et al. Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts. Oncotarget 4, 94–105 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Qiu, P. et al. Mutation detection using SurveyorTM nuclease. Biotechniques 36, 702–707 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. DuPage, M., Dooley, A.L. & Jacks, T. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat. Protoc. 4, 1064–1072 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mazur, P.K. et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc. Natl. Acad. Sci. USA 107, 13438–13443 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524–528 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Debacq-Chainiaux, F., Erusalimsky, J.D., Campisi, J. & Toussaint, O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat. Protoc. 4, 1798–1806 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Chou, T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621–681 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Chou, T.C. Drug combination sand their synergy quantification using the Chou-Talalay method. Cancer Res. 70, 440–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Carey, M.F., Peterson, C.L. & Smale, S.T. Chromatin immunoprecipitation (ChIP). Cold Spring Harbor Protoc. 10.1101/pdb.prot5279 (2009).

  77. Khatri, P. et al. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation. J. Exp. Med. 210, 2205–2221 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Storey, J.D. A direct approach to false discovery rates. J. R. Stat. Soc. B 64, 479–498 (2002).

    Article  Google Scholar 

  79. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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

Authors
  1. Pawel K Mazur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Herner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephano S Mello
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthias Wirth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simone Hausmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francisco J Sánchez-Rivera
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shane M Lofgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Timo Kuschma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephan A Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Deepak Vangala
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marija Trajkovic-Arsic
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Aayush Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Irina Heid
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Peter B Noël
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rickmer Braren
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mert Erkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jörg Kleeff
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Bence Sipos
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Leanne C Sayles
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Mathias Heikenwalder
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Elisabeth Heßmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Volker Ellenrieder
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Irene Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Tyler Jacks
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. James E Bradner
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Purvesh Khatri
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. E Alejandro Sweet-Cordero
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Laura D Attardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Roland M Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Guenter Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Julien Sage
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Jens T Siveke
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–15 (PDF 36873 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3952

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer