Preclinical Characterization of BET Family Bromodomain Inhibitor ABBV-075 Suggests Combination Therapeutic Strategies

被引：107

作者：

Bui, Mai H. ^{[1
]}

Lin, Xiaoyu ^{[1
]}

Albert, Daniel H. ^{[1
]}

Li, Leiming ^{[1
]}

Lam, Lloyd T. ^{[1
]}

Faivre, Emily J. ^{[1
]}

Warder, Scott E. ^{[1
]}

Huang, Xiaoli ^{[1
]}

Wilcox, Denise ^{[1
]}

Donawho, Cherrie K. ^{[1
]}

Sheppard, George S. ^{[1
]}

Wang, Le ^{[1
]}

Fidanze, Steve ^{[1
]}

Pratt, John K. ^{[1
]}

Liu, Dachun ^{[1
]}

Hasvold, Lisa ^{[1
]}

Uziel, Tamar ^{[1
]}

Lu, Xin ^{[1
]}

Kohlhapp, Fred ^{[1
]}

Fang, Guowei ^{[1
]}

Elmore, Steven W. ^{[1
]}

Rosenberg, Saul H. ^{[1
]}

McDaniel, Keith F. ^{[1
]}

Kati, Warren M. ^{[1
]}

Shen, Yu ^{[1
]}

机构：

[1] AbbVie Inc, Oncol Discovery, N Chicago, IL USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 11期

关键词：

PROTEIN BRD4; SELECTIVE-INHIBITION; GENE-TRANSCRIPTION; DOSE-ESCALATION; ACUTE-LEUKEMIA; P-TEFB; C-MYC; CANCER; RESISTANCE; OTX015;

D O I：

10.1158/0008-5472.CAN-16-1793

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell-cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma, and multiple myeloma cells. Apoptosis induced by ABBV075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B-cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy. (C) 2017 AACR.

引用

页码：2976 / 2989

页数：14

共 39 条

[31] Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer [J].

Shu, Shaokun ;

Lin, Charles Y. ;

He, Housheng Hansen ;

Witwicki, Robert M. ;

Tabassum, Doris P. ;

Roberts, Justin M. ;

Janiszewska, Michalina ;

Huh, Sung Jin ;

Liang, Yi ;

Ryan, Jeremy ;

Doherty, Ernest ;

Mohammed, Hisham ;

Guo, Hao ;

Stover, Daniel G. ;

Ekram, Muhammad B. ;

Peluffo, Guillermo ;

Brown, Jonathan ;

D'Santos, Clive ;

Krop, Ian E. ;

Dillon, Deborah ;

McKeown, Michael ;

Ott, Christopher ;

Qi, Jun ;

Ni, Min ;

Rao, Prakash K. ;

Duarte, Melissa ;

Wu, Shwu-Yuan ;

Chiang, Cheng-Ming ;

Anders, Lars ;

Young, Richard A. ;

Winer, Eric P. ;

Letai, Antony ;

Barry, William T. ;

Carroll, Jason S. ;

Long, Henry W. ;

Brown, Myles ;

Liu, X. Shirley ;

Meyer, Clifford A. ;

Bradner, James E. ;

Polyak, Kornelia .

NATURE, 2016, 529 (7586) :413-+

[32]

Singh BN, 2010, EXPERT REV ANTICANC, V10, P935, DOI [10.1586/era.10.62, 10.1586/ERA.10.62]

[33] Endogenous Myc maintains the tumor microenvironment [J].

Sodir, Nicole M. ;

Swigart, Lamorna Brown ;

Karnezis, Anthony N. ;

Hanahan, Douglas ;

Evan, Gerard I. ;

Soucek, Laura .

GENES & DEVELOPMENT, 2011, 25 (09) :907-916

[34] ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets [J].

Souers, Andrew J. ;

Leverson, Joel D. ;

Boghaert, Erwin R. ;

Ackler, Scott L. ;

Catron, Nathaniel D. ;

Chen, Jun ;

Dayton, Brian D. ;

Ding, Hong ;

Enschede, Sari H. ;

Fairbrother, Wayne J. ;

Huang, David C. S. ;

Hymowitz, Sarah G. ;

Jin, Sha ;

Khaw, Seong Lin ;

Kovar, Peter J. ;

Lam, Lloyd T. ;

Lee, Jackie ;

Maecker, Heather L. ;

Marsh, Kennan C. ;

Mason, Kylie D. ;

Mitten, Michael J. ;

Nimmer, Paul M. ;

Oleksijew, Anatol ;

Park, Chang H. ;

Park, Cheol-Min ;

Phillips, Darren C. ;

Roberts, Andrew W. ;

Sampath, Deepak ;

Seymour, John F. ;

Smith, Morey L. ;

Sullivan, Gerard M. ;

Tahir, Stephen K. ;

Tse, Chris ;

Wendt, Michael D. ;

Xiao, Yu ;

Xue, John C. ;

Zhang, Haichao ;

Humerickhouse, Rod A. ;

Rosenberg, Saul H. ;

Elmore, Steven W. .

NATURE MEDICINE, 2013, 19 (02) :202-208

[35] Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628 [J].

Stathis, Anastasios ;

Zucca, Emanuele ;

Bekradda, Mohamed ;

Gomez-Roca, Carlos ;

Delord, Jean-Pierre ;

Rouge, Thibault de La Motte ;

Uro-Coste, Emmanuelle ;

de Braud, Filippo ;

Pelosi, Giuseppe ;

French, Christopher A. .

CANCER DISCOVERY, 2016, 6 (05) :492-500

[36]

Wang L, 2014, BROMODOMAIN INHIBITO

[37] Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein brd4 [J].

Yang, ZY ;

Yik, JHN ;

Chen, RC ;

He, NH ;

Jang, MK ;

Ozato, K ;

Zhou, Q .

MOLECULAR CELL, 2005, 19 (04) :535-545

[38] Down-regulation of NF-κB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition [J].

Zhang, Guangtao ;

Liu, Ruijie ;

Zhong, Yifei ;

Plotnikov, Alexander N. ;

Zhang, Weijia ;

Zeng, Lei ;

Rusinova, Elena ;

Gerona-Nevarro, Guillermo ;

Moshkina, Natasha ;

Joshua, Jennifer ;

Chuang, Peter Y. ;

Ohlmeyer, Michael ;

He, John Cijiang ;

Zhou, Ming-Ming .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (34) :28840-28851

[39] RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia [J].

Zuber, Johannes ;

Shi, Junwei ;

Wang, Eric ;

Rappaport, Amy R. ;

Herrmann, Harald ;

Sison, Edward A. ;

Magoon, Daniel ;

Qi, Jun ;

Blatt, Katharina ;

Wunderlich, Mark ;

Taylor, Meredith J. ;

Johns, Christopher ;

Chicas, Agustin ;

Mulloy, James C. ;

Kogan, Scott C. ;

Brown, Patrick ;

Valent, Peter ;

Bradner, James E. ;

Lowe, Scott W. ;

Vakoc, Christopher R. .

NATURE, 2011, 478 (7370) :524-U124

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