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

Pawel K. Mazur, Alexander Herner, Stephano S. Mello, Matthias Wirth, Simone Hausmann, Francisco J. Sánchez-Rivera, Shane M. Lofgren, Timo Kuschma, Stephan A. Hahn, Deepak Vangala, Marija Trajkovic-Arsic, Aayush Gupta, Irina Heid, Peter B. Noël, Rickmer Braren, Mert Erkan, Jörg Kleeff, Bence Sipos, Leanne C. Sayles, Mathias HeikenwalderElisabeth Heßmann, Volker Ellenrieder, Irene Esposito, Tyler Jacks, James E. Bradner, Purvesh Khatri, E. Alejandro Sweet-Cordero, Laura D. Attardi, Roland M. Schmid, Guenter Schneider, Julien Sage, Jens T. Siveke

Research output: Contribution to journalArticlepeer-review

311 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1163-1171
Number of pages9
JournalNature medicine
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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