Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors

Michele Ceribelli; Priscilla N. Kelly; Arthur L. ShafferGeorge W. WrightWenming XiaoYibin YangLesley A. Mathews GrinerRajarshi GuhaPaul ShinnJonathan M. KellerDongbo LiuParesma R. PatelMarc FerrerShivangi JoshiSujata NerlePeter SandyEmmanuel NormantCraig J. ThomasLouis M. Staudt

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors

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Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors

机译：Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors

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In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-κB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IκB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-κB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第31期|11365-11370|共6页
作者
Michele Ceribelli; Priscilla N. Kelly; Arthur L. ShafferGeorge W. WrightWenming XiaoYibin YangLesley A. Mathews GrinerRajarshi GuhaPaul ShinnJonathan M. KellerDongbo LiuParesma R. PatelMarc FerrerShivangi JoshiSujata NerlePeter SandyEmmanuel NormantCraig J. ThomasLouis M. Staudt;
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作者单位

Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

Biometric Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892Constellation Pharmaceuticals, Inc., Cambridge, MA 02142;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
cancer therapy; drug synergism;

Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors

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