The Bromodomain Inhibitor, INCB057643, Targets Both Cancer Cells and the Tumor Microenvironment in Two Preclinical Models of Pancreatic Cancer.

Abstract

Simple SummaryPancreatic cancer remains a highly lethal disease, with only ~10% of patients still alive five years after diagnosis, as most patients already have advanced, metastatic disease at the time of diagnosis. Therefore, new treatments are needed for these patients. We tested INCB057643, a novel bromodomain inhibitor, in a relevant mouse model of pancreatic cancer, and this compound improves survival and reduces metastasis. Pancreatic cancers are very dense, as the stroma within the tumor can account for up to 90% of the tumor mass and is responsible for the failure of many drugs. INCB057643 modulates the immune cells within the tumor so they can attack and kill tumor cells. INCB057643 also alters immune cells within the pancreas in a mouse model of pancreatitis, which is inflammation of the pancreas that can promote the development of pancreatic cancer.In pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive phenotype. Bromodomain inhibitors are a class of drugs that target BET (bromodomain and extra-terminal) proteins, impairing their ability to bind to acetylated lysines and therefore interfering with transcriptional initiation and elongation. INCB057643 is a new generation, orally bioavailable BET inhibitor that was developed for treating patients with advanced malignancies. KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice mimic human disease, with similar progression and incidence of metastasis. Treatment of established tumors in KPC mice with INCB057643 increased survival by an average of 55 days, compared to the control group. Moreover, INCB057643 reduced metastatic burden in these mice. KPC mice treated with INCB057643, starting at 4 weeks of age, showed beneficial changes in immune cell populations in the pancreas and liver. Similarly, INCB057643 modified immune cell populations in the pancreas of KrasG12D/+; Pdx-1-Cre (KC) mice with pancreatitis, an inflammatory process known to promote pancreatic cancer progression. The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer.