Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma
Open Access
- 21 September 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 21 (10), 1163-1171
- https://doi.org/10.1038/nm.3952
Abstract
The bromodomain and extraterminal (BET) inhibitor JQ1 synergizes with the histone deacetylase inhibitor SAHA to suppress tumor growth in mouse models of pancreatic cancer. 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.Keywords
This publication has 83 references indexed in Scilit:
- Pancreatic cancer genomes reveal aberrations in axon guidance pathway genesNature, 2012
- Small-Molecule Inhibition of BRDT for Male ContraceptionCell, 2012
- BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-MycCell, 2011
- RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemiaNature, 2011
- Pancreatitis-Induced Inflammation Contributes to Pancreatic Cancer by Inhibiting Oncogene-Induced SenescenceCancer Cell, 2011
- Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and ProgressionCancer Cell, 2011
- Stage-specific sensitivity to p53 restoration during lung cancer progressionNature, 2010
- Selective inhibition of BET bromodomainsNature, 2010
- Context-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-RasCancer Cell, 2009
- Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult MiceCancer Cell, 2007