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Ref Type Journal Article
PMID (27626654)
Authors Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG, Allegrezza MJ, Yokoyama Y, Kossenkov AV, Bradner JE, Conejo-Garcia JR, Zhang R
Title BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.
Journal Vol Issue Date Pages Journal Short Title
Cell reports 16 11 2016 Sep 13 2829-2837 Cell Rep
URL
Abstract Text Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CD274 positive ovarian cancer predicted - sensitive JQ1 Preclinical Actionable In a preclinical study, JQ1 suppressed CD274 (PD-L1) expression in human ovarian cancer cell lines in culture, and inhibited CD274 (PD-L1) expression in both immune cells and tumor cells in syngeneic mouse models of ovarian cancer, resulted in cytotoxic T Cell-dependent inhibition of tumor progression (PMID: 27626654). 27626654