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

Chen‐Song Huang,Jie‐Qin Wang,Wei Zhao,Jun Wu,Shi‐Jin Li,Xinru You,Qiong‐Cong Xu,Li Wang,Fuxi Li,Xi‐Tai Huang,Xiao‐Yu Yin,Zhuoxing Gao,Chunlei Dai

doi:10.1002/advs.201902926

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, encapsulation efficiency, morphology, drug release profiles, and drug uptake in vitro. Compared to conventional free drug formulation, the nanodelivery system dramatically reduces the hepatotoxicity while significantly enhancing the tumor inhibition effects and the bioavailability of incorporated JQ1 and THZ1 at equal doses in a Gemcitabine‐resistant PDAC patient‐derived xenograft (PDX) model. Overall, the present study demonstrates that the J/T@8P4s can be a promising therapeutic treatment against the PDAC via suppression of SE‐associated oncogenic transcription, and provides a strategy utilizing NPs to assist the drug delivery targeting SEs.

Highlights

Pancreatic ductal adenocarcinoma (PDAC), a painful and fatal malignancy with high mortality, accounts for more than 90% pancreatic cancer
Its incidence is increasing in recent years, and it is estimated that PDAC will be ranked as the second cause of cancer death in the world by 2020.[1] genomic sequencing has improved the understanding of PDAC genetic abnormalities, few targetable targets have been found.[2]
Due to the misregulated transcription factors (TFs) play dominant roles in driving and maintaining PDAC, we aimed to identify a candidate list of transcription factor genes associated with SEs

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC), a painful and fatal malignancy with high mortality, accounts for more than 90% pancreatic cancer. Its incidence is increasing in recent years, and it is estimated that PDAC will be ranked as the second cause of cancer death in the world by 2020.[1] genomic sequencing has improved the understanding of PDAC genetic abnormalities, few targetable targets have been found.[2]. There are no clinically available molecular targeting drugs for PDAC patients. A better understanding of the complex mechanisms underlying the progress of PDAC, such as the effect of epigenomic changes on the oncogenic transcription, is urgently needed for the development of effective treatment. The hallmarks of cancer cells phenotypes (unlimited proliferation, replicative immortality, apoptosis evasion, and metastasis) are caused by aberrant regulation of gene expression.

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