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

Huang, Chen‐Song; You, Xinru; Dai, Chenyang; Xu, Qiong‐Cong; Li, Fuxi; Wang, Li; Huang, Xi‐Tai; Wang, Jie‐Qin; Li, Shijin; Gao, Zhuoxing; Wu, Jun; Yin, Xiaoyu; Zhao, Wei

doi:10.1002/advs.201902926

Cited by 43 publications

(42 citation statements)

References 31 publications

(15 reference statements)

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“…The effectiveness of JQ1 has been reported in many previous studies (16)(17)(18)(19)(20)(21), including those of gastric cancer (16,17). OTX015, another BRD4 inhibitor, shows a wide range of antitumor activities (22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 84%

“…A series of highly specific inhibitors of BRD4 have been researched and developed. For instance, JQ1 could target tumor-related genes specific for super enhancers and inhibit tumor proliferation and migration in various cancers (14,15), including gastric cancer (16,17), breast cancer (18), medulloblastoma (19), pancreatic ductal adenocarcinoma (20), and renal cell carcinoma (21). The BRD4 inhibitor OTX015 is in ongoing phase I clinical trials to treat patients with not only solid tumors but also hematological malignancies and shows a wide range of antitumor activities (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

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ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways

et al. 2021

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ObjectiveSuppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.MethodsCell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.ResultsThe messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.ConclusionsHigh mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways

et al. 2021

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“…For testing synergistic effect of OICR-9429 and cisplatin, the PCa cells were treated with each drug alone or in combination and then the cell viability was measured by MTT assay. The Combinational Index (CI) was calculated by using CalcuSyn software (Biosoft) and CI<1.0 was considered to be synergistic effect 45 .…”

Section: Methodsmentioning

confidence: 99%

WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer

Zhou

Chen

et al. 2021

Theranostics

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Purpose: Advanced prostate cancer (PCa) has limited treatment regimens and shows low response to chemotherapy and immunotherapy, leading to poor prognosis. Histone modification is a vital mechanism of gene expression and a promising therapy target. In this study, we characterized WD repeat domain 5 (WDR5), a regulator of histone modification, and explored its potential therapeutic value in PCa. Experimental Design: We characterized specific regulators of histone modification, based on TCGA data. The expression and clinical features of WDR5 were analyzed in two dependent cohorts. The functional role of WDR5 was further investigated with siRNA and OICR-9429, a small molecular antagonist of WDR5, in vitro and in vivo . The mechanism of WDR5 was explored by RNA-sequencing and chromatin immunoprecipitation (ChIP). Results: WDR5 was overexpressed in PCa and associated with advanced clinicopathological features, and predicted poor prognosis. Both inhibition of WDR5 by siRNA and OICR-9429 could reduce proliferation, and increase apoptosis and chemosensitivity to cisplatin in vitro and in vivo . Interestingly, targeting WDR5 by siRNA and OICR-9429 could block IFN-γ-induced PD-L1 expression in PCa cells. Mechanistically, we clarified that some cell cycle, anti-apoptosis, DNA repair and immune related genes, including AURKA, CCNB1, E2F1, PLK1, BIRC5, XRCC2 and PD-L1, were directly regulated by WDR5 and OICR-9429 in H3K4me3 and c-Myc dependent manner. Conclusions: These data revealed that targeting WDR5 suppressed proliferation, enhanced apoptosis, chemosensitivity to cisplatin and immunotherapy in PCa. Therefore, our findings provide insight into OICR-9429 is a multi-potency and promising therapy drug, which improves the antitumor effect of cisplatin or immunotherapy in PCa.

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“…Alternatively, drug release may be triggered endogenously through construction of nanoparticles with pH- [ 67 ], redox- [ 68 , 69 , 70 ], hypoxia- [ 71 , 72 ] or enzyme-responsive [ 73 ] properties. The combined potential for tumour-selective drug delivery via these mechanisms can lead to several benefits, including a reduction in off-target effects that often manifest as intolerable, treatment-limiting toxicities in those receiving conventional therapy [ 74 , 75 , 76 ].…”

Section: Advantages Of Nanoparticle-based Therapiesmentioning

confidence: 99%

Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance

Greene

Johnston

Scott

2021

Cancers

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The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours.

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

Cited by 43 publications

References 31 publications

ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways

ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways

WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer

Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance

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