Original ArticleBromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer

- Bromodomain inhibitors JQ1 and I-BET 762 decreased c-myc and p-Erk 1/2 proteins and inhibited proliferation in pancreatic cancer cells
- These molecules suppress the production of nitric oxide and inflammatory cytokines in immune and pancreatic cancer cells
- JQ1 and I-BET 762 reduced protein levels of IL-6, p-Erk 1/2 and p-Stat 3 in mouse models of pancreatic cancer
- I-BET 762 reduced the levels of tumor-promoting immune cells in a caerulein-induced preclinical model of pancreatitis

Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of selective, small molecule inhibitors that target BET (bromodomain and extra terminal) proteins. By impairing their ability to bind to acetylated lysines on histones, bromodomain inhibitors interfere with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. In this study, JQ1 and I-BET 762 decreased c-Myc and p-Erk 1/2 protein levels and inhibited proliferation in pancreatic cancer cells. The tumor microenvironment is known to play an important role in pancreatic cancer, and these drugs suppressed the production of nitric oxide and a variety of inflammatory cytokines, including IL-6, CCL2, and GM-CSF, in both immune and pancreatic cancer cells in vitro. Notably, the bromodomain inhibitors also reduced protein levels of p-Erk 1/2 and p-STAT3 in mouse models of pancreatic cancer. All of these proteins are essential for tumor promotion, progression and metastasis. In conclusion, the bromodomain inhibitors JQ1 and I-BET 762 targeted and suppressed multiple pathways in pancreatic cancer. I-BET 762 and a number of other bromodomain inhibitors are currently being tested in several clinical trials, making them potentially promising drugs for the treatment of pancreatic cancer, an often-fatal disease.