Details

Autor(en) / Beteiligte

• Bui, Mai H
• Lin, Xiaoyu
• Albert, Daniel H
• Li, Leiming
• Lam, Lloyd T
• Faivre, Emily J
• Warder, Scott E
• Huang, Xiaoli
• Wilcox, Denise
• Donawho, Cherrie K
• Sheppard, George S
• Wang, Le
• Fidanze, Steve
• Pratt, John K
• Liu, Dachun
• Hasvold, Lisa
• Uziel, Tamar
• Lu, Xin
• Kohlhapp, Fred
• Fang, Guowei
• Elmore, Steven W
• Rosenberg, Saul H
• McDaniel, Keith F
• Kati, Warren M
• Shen, Yu

Titel

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

Ist Teil von

• Cancer research (Chicago, Ill.), 2017-06, Vol.77 (11), p.2976-2989

Ort / Verlag

United States: American Association for Cancer Research, Inc

Erscheinungsjahr

2017

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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 G 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 ABBV-075 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. combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of synergy between ABBV-075 and these agents. The / 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. .