Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

Kregel, Steven; Malik, Rohit; Asangani, Irfan A.; Wilder-Romans, Kari; Rajendiran, Thekkelnaycke M.; Xiao, Lanbo; Vo, Josh N.; Soni, Tanu; Cieślik, Marcin; Fernadez-Salas, Ester; Cao, Xuhong; Speers, Corey; Wang, Shaomeng; Chinnaiyan, Arul M.

doi:10.1158/1078-0432.ccr-18-3776

Cited by 28 publications

(28 citation statements)

References 49 publications

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“…Together, these data suggested that, like AR-targeting compounds, BET inhibitors may possess therapeutic potential for mitigating SARS-CoV-2 infection. We thus used the SARS-CoV-2 bioassay platform to evaluate the antiviral effects of BET inhibitors (JQ1, OTX015) and a BET protein degrader (ZBC260) ( 29 ). JQ1, OTX015, and ZBC260 all decreased the infectivity of SARS-CoV-2 in LNCaP cells, with IC 50 values of 10, 8, and 3.5 nM, respectively ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting transcriptional regulation of SARS-CoV-2 entry factorsACE2andTMPRSS2

Qiao

Wang

Mannan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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164

176

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.

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Section: Resultsmentioning

confidence: 99%

Targeting transcriptional regulation of SARS-CoV-2 entry factorsACE2andTMPRSS2

Qiao

Wang

Mannan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

164

176

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“…Knowledge of circRNA involvement in pathogenetic mechanisms of cancer ( Kregel et al, 2019 ) and leukemia, such as AML ( Guarnerio et al, 2016 ; Sun et al, 2019 ; Yi et al, 2019 ) and acute lymphoblastic leukemia (ALL) ( Hirsch et al, 2017 ; Gaffo et al, 2019 ; Molin et al, 2019 ) (make circRNAs extremely attractive molecules for translational research in oncohematology ( Bonizzato et al, 2016 ; Kristensen et al, 2018 )). In this study we used total RNA sequencing to uncover the circRNA transcriptome in 19 JMML patients of four molecular subtypes and their potential role in JMML disease.…”

Section: Discussionmentioning

confidence: 99%

CircRNAs Dysregulated in Juvenile Myelomonocytic Leukemia: CircMCTP1 Stands Out

Molin

Hofmans

Gaffo

et al. 2021

Front. Cell Dev. Biol.

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Juvenile myelomonocytic leukemia (JMML), a rare myelodysplastic/myeloproliferative neoplasm of early childhood, is characterized by clonal growth of RAS signaling addicted stem cells. JMML subtypes are defined by specific RAS pathway mutations and display distinct gene, microRNA (miRNA) and long non-coding RNA expression profiles. Here we zoom in on circular RNAs (circRNAs), molecules that, when abnormally expressed, may participate in malignant deviation of cellular processes. CirComPara software was used to annotate and quantify circRNAs in RNA-seq data of a “discovery cohort” comprising 19 JMML patients and 3 healthy donors (HD). In an independent set of 12 JMML patients and 6 HD, expression of 27 circRNAs was analyzed by qRT-PCR. CircRNA-miRNA-gene networks were reconstructed using circRNA function prediction and gene expression data. We identified 119 circRNAs dysregulated in JMML and 59 genes showing an imbalance of the circular and linear products. Our data indicated also circRNA expression differences among molecular subgroups of JMML. Validation of a set of deregulated circRNAs in an independent cohort of JMML patients confirmed the down-regulation of circOXNAD1 and circATM, and a marked up-regulation of circLYN, circAFF2, and circMCTP1. A new finding in JMML links up-regulated circMCTP1 with known tumor suppressor miRNAs. This and other predicted interactions with miRNAs connect dysregulated circRNAs to regulatory networks. In conclusion, this study provides insight into the circRNAome of JMML and paves the path to elucidate new molecular disease mechanisms putting forward circMCTP1 up-regulation as a robust example.

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“…Interestingly, ARV-771—a small-molecule pan-BET degrader based on proteolysis-targeting chimera technology—displayed a consistently improved efficacy in cellular models of CRPC, compared to classical BET inhibition [290]. Particularly, CRBN-mediated BET degraders have increased specificity and efficacy in CRPC, as compared to traditional BET inhibitors or other types of degraders [291]. Importantly, treatment with the CRBN-mediated degraders on prostate cancer cells induces a pronounced inhibitory effect on both AR and MYC signaling axes and elicited a markedly inhibitory effect on cell growth and stimulatory on cell apoptosis [291].…”

Section: Most Recurrent Genetic Abnormalities Observed In Prostatementioning

confidence: 99%

“…Particularly, CRBN-mediated BET degraders have increased specificity and efficacy in CRPC, as compared to traditional BET inhibitors or other types of degraders [291]. Importantly, treatment with the CRBN-mediated degraders on prostate cancer cells induces a pronounced inhibitory effect on both AR and MYC signaling axes and elicited a markedly inhibitory effect on cell growth and stimulatory on cell apoptosis [291].…”

Section: Most Recurrent Genetic Abnormalities Observed In Prostatementioning

confidence: 99%

“…In view of possible clinical applications, it is of fundamental importance to identify highly active BET inhibitors that can be used at low concentrations. In this context, two different reports described BET protein degraders able in vitro and in vivo to suppress AR and MYC signaling at lower concentrations than classical BET inhibitors [290,291].…”

Section: Novel Therapies For Prostate Cancermentioning

confidence: 99%

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Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

Cited by 28 publications

References 49 publications

Targeting transcriptional regulation of SARS-CoV-2 entry factorsACE2andTMPRSS2

Targeting transcriptional regulation of SARS-CoV-2 entry factorsACE2andTMPRSS2

CircRNAs Dysregulated in Juvenile Myelomonocytic Leukemia: CircMCTP1 Stands Out

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

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