The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice

In pancreatic cancer, the tumor microenvironment (TME) comprises up to 90% of the tumor mass. Pancreatitis, marked by increased macrophage infiltration into the pancreas, is a recognized risk factor for developing pancreatic cancer. The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) plays a crucial role in responding to oxidative stress and can contribute to cancer progression and chemoresistance. NRF2 also mitigates inflammation by regulating macrophage-specific genes. Heme oxygenase 1 (HO-1), expressed by anti-inflammatory macrophages, degrades heme, and its expression relies on NRF2′s translocation to the nucleus. In macrophages exposed to conditioned media from pancreatic cancer cells, levels of HO-1 protein increased, correlating with elevated NRF2 expression in the nuclear fraction. Notable differences in macrophage infiltration and HO-1 expression were observed in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice, and wild-type mice with pancreatitis. Given that tumors often utilize epigenetic modulation to influence the TME, employing small molecules as epigenetic modulators to enhance immune recognition is therapeutically appealing. Treatment with the bromodomain inhibitor I-BET-762 in macrophages or mice with pancreatitis resulted in reduced HO-1 levels. This study demonstrates that bromodomain inhibitors can mitigate physiological responses to inflammation that promote tumorigenesis.