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

被引：164

作者：

Ceribelli, Michele ^{[1
]}

Kelly, Priscilla N. ^{[1
]}

Shaffer, Arthur L. ^{[1
]}

Wright, George W. ^{[2
]}

Xiao, Wenming ^{[1
]}

Yang, Yibin ^{[1
]}

Griner, Lesley A. Mathews ^{[3
]}

Guha, Rajarshi ^{[3
]}

Shinn, Paul ^{[3
]}

Keller, Jonathan M. ^{[3
]}

Liu, Dongbo ^{[3
]}

Patel, Paresma R. ^{[3
]}

Ferrer, Marc ^{[3
]}

Joshi, Shivangi ^{[4
]}

Nerle, Sujata ^{[4
]}

Sandy, Peter ^{[4
]}

Normant, Emmanuel ^{[4
]}

Thomas, Craig J. ^{[3
]}

Staudt, Louis M. ^{[1
]}

机构：

[1] Natl Canc Inst, Lymphoid Malignancies Branch, NIH, Bethesda, MD 20892 USA

[2] Natl Canc Inst, Biometr Res Branch, NIH, Bethesda, MD 20892 USA

[3] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bethesda, MD 20892 USA

[4] Constellat Pharmaceut Inc, Cambridge, MA 02142 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 31期

基金：

美国国家卫生研究院;

关键词：

cancer therapy; drug synergism; GENE-EXPRESSION; SELECTIVE-INHIBITION; BET BROMODOMAINS; SUPER-ENHANCERS; MYC; TRANSCRIPTION; LEUKEMIA; DISCOVERY; TARGET; BRD4;

D O I：

10.1073/pnas.1411701111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-kappa B activity is essential for viability of the malignant cells and is sustained by constitutive activity of I kappa B 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-kappa B-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.

引用

页码：11365 / 11370

页数：6

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