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Ref Type Journal Article
PMID (31000582)
Authors Bevill SM, Olivares-Quintero JF, Sciaky N, Golitz BT, Singh D, Beltran AS, Rashid NU, Stuhlmiller TJ, Hale A, Moorman NJ, Santos CM, Angus SP, Zawistowski JS, Johnson GL
Title GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer.
Journal Molecular cancer research : MCR
Vol 17
Issue 7
Date 2019 07
URL
Abstract Text Screening of an inhibitor library targeting kinases and epigenetic regulators identified several molecules having antiproliferative synergy with extraterminal domain (BET) bromodomain (BD) inhibitors (JQ1, OTX015) in triple-negative breast cancer (TNBC). GSK2801, an inhibitor of BAZ2A/B BDs, of the imitation switch chromatin remodeling complexes, and BRD9, of the SWI/SNF complex, demonstrated synergy independent of BRD4 control of P-TEFb-mediated pause-release of RNA polymerase II. GSK2801 or RNAi knockdown of BAZ2A/B with JQ1 selectively displaced BRD2 at promoters/enhancers of ETS-regulated genes. Additional displacement of BRD2 from rDNA in the nucleolus coincided with decreased 45S rRNA, revealing a function of BRD2 in regulating RNA polymerase I transcription. In 2D cultures, enhanced displacement of BRD2 from chromatin by combination drug treatment induced senescence. In spheroid cultures, combination treatment induced cleaved caspase-3 and cleaved PARP characteristic of apoptosis in tumor cells. Thus, GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces apoptosis of TNBC. IMPLICATIONS: Synergistic inhibition of BDs encoded in BAZ2A/B, BRD9, and BET proteins induces apoptosis of TNBC by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes.

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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
BAZ2-ICR BAZ2-ICR is a selective BAZ2A and BAZ2B bromodomain inhibitor, which has potential antitumor activity (PMID: 31000582).
BI-9564 BI9564|BI 9564 BI-9564 is a selective BRD9 inhibitor that also has activity against BRD7 and CECR2, which has potential antitumor activity (PMID: 31000582, PMID: 26749027, PMID: 26914985).
CPI-637 CPI637|CPI 637 CPI-637 is a CBP/p300 bromodomain inhibitor, which may have antitumor activity (PMID: 31000582).
GSK2801 GSK 2801|GSK-2801 GSK2801 is a bromodomain inhibitor that selectively inhibits BAZ2A/B and BRD9, which has potential antitumor activity (PMID: 31000582).
HY-16462 HY16462|HY 16462 CDK9 Inhibitor 16 HY-16462 is a CDK9 inhibitor, which has potential antitumor activity (PMID: 31000582).
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
Unknown unknown triple-receptor negative breast cancer not applicable Birabresib + GSK2801 Preclinical - Cell culture Actionable In a preclinical study, Birabresib (OTX015) and GSK2801 treatment synergistically inhibited growth of a triple-negative breast cancer cell line in culture (PMID: 31000582). 31000582
Unknown unknown triple-receptor negative breast cancer not applicable HY-16462 + JQ1 Preclinical - Cell culture Actionable In a preclinical study, HY-16462 and JQ1 treatment synergistically inhibited growth of a triple-negative breast cancer cell line in culture (PMID: 31000582). 31000582
Unknown unknown triple-receptor negative breast cancer not applicable BAZ2-ICR + JQ1 Preclinical - Cell culture Actionable In a preclinical study, BAZ2-ICR and JQ1 combination treatment inhibited Rb1 phosphorylation, and induced moderate growth inhibition and cellular senescence in triple-negative breast cancer cell lines in culture (PMID: 31000582). 31000582
Unknown unknown triple-receptor negative breast cancer not applicable GSK2801 + JQ1 Preclinical - Cell culture Actionable In a preclinical study, GSK2801 and JQ1 treatment synergistically inhibited cell growth and viability, led to enhanced cell cycle arrest, and induced senescence and apoptosis in triple-negative breast cancer cell lines in culture (PMID: 31000582). 31000582
Unknown unknown triple-receptor negative breast cancer not applicable CPI-637 + HY-16462 Preclinical - Cell culture Actionable In a preclinical study, CPI-637 and HY-16462 treatment synergistically inhibited growth of a triple-negative breast cancer cell line in culture (PMID: 31000582). 31000582
Unknown unknown triple-receptor negative breast cancer not applicable BAZ2-ICR + BI-9564 + JQ1 Preclinical - Cell culture Actionable In a preclinical study, BAZ2-ICR treatment combined with BI-9564 and JQ1 inhibited Rb1 phosphorylation, induced senescence and complete growth inhibition, and led to enhanced cell cycle arrest in triple-negative breast cancer cell lines in culture (PMID: 31000582). 31000582
Unknown unknown triple-receptor negative breast cancer no benefit GSK2801 + HY-16462 Preclinical - Cell culture Actionable In a preclinical study, GSK2801 and HY-16462 combination treatment did not synergistically inhibit growth of a triple-negative breast cancer cell line in culture (PMID: 31000582). 31000582