Targeting MYC Dependence in Cancer by Inhibiting BET Bromodomains

Constellation Pharmaceuticals, Inc, Cambridge, MA 02142, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2011; 108(40):16669-74. DOI: 10.1073/pnas.1108190108
Source: PubMed


The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein-DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G(1) arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.

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Available from: Jennifer A Mertz, Mar 12, 2014
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    • "Similarly, follow-up studies by Dawson and colleagues demonstrated that I-BET151 confers a significant survival advantage and reduces the circulating leukemic burden in a murine model of AML (Dawson et al., 2014). These experiments will be replicated in Protocols 4 and 5. Similar studies testing the efficacy of JQ1, an independent BET inhibitor, reported a decrease in tumor growth in nude mice bearing AML xenografts (MV4;11 cells) (Mertz et al., 2011) and SCID-beige mice bearing MM xenografts (MM.1S cells) (Delmore et al., 2011). "
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    ABSTRACT: The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from 'Inhibition of bromodomain and extra terminal (BET) recruitment to chromatin as an effective treatment for mixed-lineage leukemia (MLL)-fusion leukemia' by Dawson and colleagues, published in Nature in 2011 (Dawson et al., 2011). The experiments to be replicated are those reported in Figures 2A, 3D, 4B, 4D and Supplementary Figures 11A-B and 16A. In this study, BET proteins were demonstrated as potential therapeutic targets for modulating aberrant gene expression programs associated with MLL-fusion leukemia. In Figure 2A, the BET bromodomain inhibitor I-BET151 was reported to suppress growth of cells harboring MLL-fusions compared to those with alternate oncogenic drivers. In Figure 3D, treatment of MLL-fusion leukemia cells with I-BET151 resulted in transcriptional suppression of the anti-apoptotic gene BCL2. Figures 4B and 4D tested the therapeutic efficacy of I-BET151 in vivo using mice injected with human MLL-fusion leukemia cells and evaluated disease progression following I-BET151 treatment. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.08997 · 9.32 Impact Factor
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    • "The effect of BET inhibitors on NMC growth has led to clinical trials treating NMC (ClinicalTrials .gov identifiers NCT01587703, NCT01987362, NCT02259114) and numerous new studies indicating that many other cancer types, including more common hematopoietic and solid malignancies, are dependent on endogenous, nonmutant BRD4 for growth (Delmore et al. 2011; Mertz et al. 2011; Zuber et al. 2011; Henssen et al. 2013; Puissant et al. 2013; Asangani et al. 2014). In these non-NMC cancers, it appears that an important function of BRD4 is its association with genes that define cell identity and encode critical oncogenic driver proteins, such as MYC. "
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    ABSTRACT: NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These "megadomains" appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription. © 2015 Alekseyenko et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 07/2015; 29(14):1507-1523. DOI:10.1101/gad.267583.115 · 10.80 Impact Factor
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    • "JQ1 is known to competitively bind to the acetyl-lysine recognition pocket within BRD4's bromodomains, leading to the dissociation of the BRD4-P-TEFb complex from acetylated chromatin (Zuber et al., 2011; Li et al., 2013). Consistent with the results obtained in other cell types (Mertz et al., 2011; Zuber et al., 2011), JQ1 decreased the associations of both BRD4 and CDK9 with the MYC locus in HeLa cells (Figure 4—figure supplement 2). More importantly, JQ1 also completely abolished the MYC induction by i-CDK9 in HeLa (Figure 4C) as well as the lung cancer cell line H1792 and the melanoma cell line A2058 (Figure 4—figure supplement 3), whereas the control enantiomer was ineffective in this regard. "
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    ABSTRACT: CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.
    eLife Sciences 06/2015; 4. DOI:10.7554/eLife.06535 · 9.32 Impact Factor
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