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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A novel dual epigenetic approach targeting BET proteins and HDACs in Group 3 (MYC-driven) Medulloblastoma
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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.
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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