BET bromodomain inhibition as a therapeutic strategy to target c-Myc

By Citation Delmore, J. E., Ghayas C. Issa, M. Lemieux, P. Rahl, Junwei Shi, H. M. Jacobs, J. Delmore, E. Kastritis, Timothy Gilpatrick and 16 more. Cell, 2011

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SUMMARY MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative co-activator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f38787eed0a1014990451e0c4940f01ef1cb6101

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Citations in the corpus

Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers (2013, background): “S cells with JQ1 leads to reduced levels of BRD4 at the IgH enhancer that drives MYC expression (Delmore et al., 2011), but it is not clear whether such treatment causes a general reduction in the levels of BRD4 associated with the genome.”
R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, background): “Primary AML cells with IDH mutations are also sensitive to JQ1, an inhibitor of MYC signaling (Delmore et al., 2011), often with an IC50 lower than 1 mM, thoughwith a higher IC50 than AML cells with wild-type IDH (Figure 7B; Table S4), likely due to the hyper-activation of MYC signaling in the forme”
Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family (2012, background): “Recent data strongly suggested that targeting BET BRDs will be beneficial for many diverse cancer types due to downregulation of oncogenes such as c-Myc (Dawson et al., 2011; Delmore et al., 2011; Mertz et al., 2011).”
Cancer Genetics and Epigenetics: Two Sides of the Same Coin? (2012, background): “Selective bromodomain inhibitors (JQ1 or GSK525762) (Filippakopoulos et al., 2010; Nicodeme et al., 2010) inhibit transcription by MYC, which is overexpressed in a majority of cancers (Delmore et al., 2011).”
Revisiting Global Gene Expression Analysis (2012, neutral): “These codesets encompassed sets of known cancer related genes (CodeSets CS-1 and CS-2) (Delmore et al., 2011).”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “A promising class of compounds found to suppress MYC transcription, thereby enhancing senescence, are represented by BET protein bromodomain inhibitors such as JQ1 or CPI-0610 and are currently tested in clinical trials in different cancer patients (87, 118).”
Transcriptional enhancers: from properties to genome-wide predictions (2014, background): “Cofactor occupancy at super enhancers has been shown to be particularly sensitive to cofactor inhibition (for example, by BET bromodomain inhibitors 147,148 ), which may underlie the sensitivity of acute myeloid leukaemia 149 and multiple myeloma 150 to these agents.”
The PI3K pathway in human disease (2017, positive): “Finally, primaryoracquiredresistancecanalsoarisebyactivationofheterologous pathwaysleadingtocommonendpoints;forinstance,MYC-dependent transcriptional activation or ERK activity (in pink, ‘‘4’’). mTORC2 and PDK1 and shares with AKT the ability to phosphorylate TSC2, leading to mTORC1 activation.”