Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer.

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.

Leal AS ，Williams CR ，Royce DB ，Pioli PA ，Sporn MB ，Liby KT ... -  《-》

Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer.

Yamamoto K ，Tateishi K ，Kudo Y ，Hoshikawa M ，Tanaka M ，Nakatsuka T ，Fujiwara H ，Miyabayashi K ，Takahashi R ，Tanaka Y ，Ijichi H ，Nakai Y ，Isayama H ，Morishita Y ，Aoki T ，Sakamoto Y ，Hasegawa K ，Kokudo N ，Fukayama M ，Koike K ... -  《Oncotarget》

EGFR signaling confers resistance to BET inhibition in hepatocellular carcinoma through stabilizing oncogenic MYC.

Yin Y ，Sun M ，Zhan X ，Wu C ，Geng P ，Sun X ，Wu Y ，Zhang S ，Qin J ，Zhuang Z ，Liu Y ... -  《-》

Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.

Klingbeil O ，Lesche R ，Gelato KA ，Haendler B ，Lejeune P ... -  《Cell Death & Disease》

The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects.

Patients with neuroblastoma associated with MYCN oncogene amplification experience a very poor prognosis. BET bromodomain inhibitors are among the most promising novel anticancer agents as they block BRD3 and BRD4 from activating oncogene transcription. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission in many murine models. MYCN-amplified neuroblastoma cells were treated with vehicle control, the BET bromodomain inhibitor JQ1, the histone deacetylase inhibitor panobinostat, or the combination of JQ1 and panobinostat. Genes modulated by JQ1, panobinostat, or the combination therapy were identified by Affymetrix microarray, and cell proliferation and apoptosis were examined by Alamar blue assays and flow cytometry analysis. Modulation of LIN28B promoter activity by BRD3 and BRD4 was examined by chromatin immunoprecipitation and luciferase assays. In addition, neuroblastoma-bearing mice were treated with vehicle control, JQ1, and/or panobinostat. LIN28B was one of the top genes synergistically reduced by JQ1 and panobinostat. BRD3 and BRD4 directly bound to the LIN28B gene promoter and activated LIN28B gene transcription, and knocking down LIN28B reduced the expression of N-Myc protein, but not N-Myc mRNA. JQ1 and panobinostat synergistically reduced LIN28B gene and N-Myc protein expression, and synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal nonmalignant cells in vitro In neuroblastoma-bearing mice, JQ1 and panobinostat synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression. Our findings have identified a novel strategy to reduce the N-Myc oncoprotein expression and a novel therapeutic approach for the treatment of aggressive neuroblastoma. Clin Cancer Res; 22(10); 2534-44. ©2016 AACR.

Shahbazi J ，Liu PY ，Atmadibrata B ，Bradner JE ，Marshall GM ，Lock RB ，Liu T ... -  《-》