Targeting Super-Enhancers via Nanoparticle-Facilitated BRD4 and CDK7 Inhibitors Synergistically Suppresses Pancreatic Ductal Adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant cancer with complex genomic variations, and no targetable genomic lesions have been found yet. Super-enhancers (SEs) have been found to contribute to the continuous and robust oncogenic transcription. Here, histone H3 lysine 27 acetylation (H3K27ac) is profiled in PDAC cell lines to establish SE landscapes. Concurrently, it is also shown that PDAC is vulnerable to the perturbation of the SE complex using bromodomain-containing protein 4 (BRD4) inhibitor, JQ1, synergized with cyclin-dependent kinase 7 (CDK7) inhibitor, THZ1. Formulations of hydrophobic l-phenylalanine-poly (ester amide) nanoparticles (NPs) with high drug loading of JQ1 and THZ1 (J/T@8P4s) are further designed and developed. J/T@8P4s is assessed for size, encapsul

SUBMITTER: Huang CS 

PROVIDER: S-EPMC7140991 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature