Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer

By I. Asangani, Vijaya L. Dommeti, Xiaoju Wang, Rohit Malik, M. Cieslik, Rendong Yang, J. Escara-Wilke, K. Wilder-Romans, Sudheer Dhanireddy, Carl G. Engelke and 8 more. Nature, 2014

897 citations recorded by the source corpus.

Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e7fd8cf6775172cfeada299015e00b4315523d9d

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In Molecular Biology

Citations in the corpus

Genetics and biology of prostate cancer (2018, background): “Recent studies also uncovered additional factors boosting AR transcriptional activity, including RNF6 (Xu et al. 2009), SIAH2 (Qi et al. 2013), DNA-dependent protein kinases (DNA-PKcs) (Goodwin et al. 2013, 2015), bromodomain protein BRD4 (Asangani et al. 2014, 2016), TRIM24 (Groner et al. 2016), an”
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. (2015, background): “…in multiple cancer types, including midline carcinoma, acute myeloid leukemia (AML), multiple myeloma (MM), Burkitt’s lymphoma (BL), and prostate cancer (Asangani et al., 2014; Delmore et al., 2011; French et al., 2008; Loven et al., 2013; Mertz et al., 2011; Wyce et al., 2013; Zuber et al., 2011).”
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 (2014, neutral): “, [39]; see also the DiffBind package [40, 41]), barcode-based assays (e.”
PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer (2016, background): “Two recent studies claim that BET inhibition does not alter FL-AR levels (19, 20).”