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.

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…These findings are consistent with the previous reports that show that JQ1 inhibits inflammation in pancreatic ductal adenocarcinoma [40] and a murine periodontitis model [41]. Thus, our study implicates that JQ1 might also reduce inflammation in NSCLC cells.…”

Concepts to Target MYC in Pancreatic Cancer

“…In addition to the human PdX models, JQ1 activity was recently demonstrated in a genetically engineered PDAC mouse model (GEMM). Here, MYC and proinflammatory pathways were blocked by JQ1 (12). In sum, preclinical data argue that BET-I-based therapies should be further developed.…”

“…MYC alone is sufficient to initiate tumors and to drive tumor progression in the pancreas in vivo (5,(7)(8)(9)(10). Furthermore, compelling evidence exists that MYC is an essential downstream effector of oncogenic KRAS in the pancreas (11)(12)(13)(14). MYC expression is controlled at several layers in PDAC (15).…”

Epigenetics of gastrointestinal diseases: notes from a workshop

“…Mechanistically, combined inhibition of AURKA mitotic kinase and H3K9 HMTs triggers uncoordinated checkpoint responses in G2/M, disrupting the cell cycle and leading to mitotic catastrophe. Dr. Jens Siveke presented recent work highlighting the importance of patient stratification in treating pancreatic cancer, as 30% of PDAC patients have alterations in epigenomic regulators [30]. His group showed synergism between the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) and JQ, an inhibitor of bromodomain and extraterminal (BET) proteins, in suppressing PDAC, but only in a subset of tumor xenografts.…”

“…However, transcriptome studies of PDAC samples have suggested the division of this disease into classical, quasimesenchymal, and exocrine-like subtypes on the basis of differential gene expression and histological differences within subtypes [34]. As mentioned above, Dr. Jens Siveke identified different PDAC subtypes based on differential sensitivity to drugs such as HDAC and BET inhibitors [30]. Higher levels of the lncRNA CCAT1 correlated with increased sensitivity to HDAC inhibitors, which is already used to predict sensitivity to BET inhibitors in colorectal cancers.…”