Abstract
Abstract Pancreatic cancer is expected to be the second most deadly cancer by 2030 with very few effective therapeutic options to improve patient survival. Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of chemotherapeutic drugs that target BET proteins, impairing their ability to bind to acetyl modified lysines and therefore interfering with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. I-BET 762 is currently in clinical trials for cancer and has the advantage of oral administration. Kras is one of the most common mutated genes in pancreatic cancer (90%); however its protein is a difficult drug target. p-Erk, responsible for several pathways regulating cell survival, is a downstream effector of Kras that has been shown to be essential for the progression and maintenance of pancreatic cancer. LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) and LSL-KrasG12D/+;Pdx-1-Cre (KC) mouse models are commonly used to study pancreatic cancer. KPC mice develop the full spectrum of pancreatic cancer by an average age of 20 weeks. The KC mouse model is commonly used to study pancreatic cancer progression after stimulation with a pancreatic inflammatory agent, such as cerulein. JQ1 and I-BET 762 reduce the protein levels of p-ERK 1/2 in cells lines derived from a pancreatic tumor or ascites of KPC animals. JQ1 and I-BET 762 are also effective at inhibiting cell growth in human pancreatic cells harboring Kras mutations. When KC mice are injected with LPS to induce inflammation and pancreatitis, p-ERK 1/2 protein levels are significantly increased. This model is being used to test the effects of JQ1 and I-BET 762 after a single LPS injection, in KC mice. Pancreatic cancer is driven by several cytokines and chemokines, including CCL2 and IL-6, which recruit and regulate the inflammatory cells (macrophages, T cells and MDSC (Myeloid derived suppressor cells) cells) in the tumor. Levels of IL-6 and CCL2 in cell lines developed from KPC mice are reduced when treated with JQ1 and I-BET 762. KC mice stimulated with LPS also have higher levels of CCL2 and IL-6 than mice stimulated with saline. In conclusion this study showed that the bromodomain inhibitors JQ1 and I-BET 762 had positive effects in suppressing targets of inflammation in pancreatic cancer. We thank James Bradner for the generous gift of JQ1. Citation Format: Ana S. Leal, Charlotte R. Williams, Michael B. Sporn, Karen T. Liby. Therapeutic effects of the bromodomain inhibitors JQ1 and I-BET 762 on pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 293. doi:10.1158/1538-7445.AM2015-293
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