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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.

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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.

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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.

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

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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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