Abstract:
: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 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. 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. Cancer Res; 77(11); 2976-89. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Bui MH,Lin X,Albert DH,Li L,Lam LT,Faivre EJ,Warder SE,Huang X,Wilcox D,Donawho CK,Sheppard GS,Wang L,Fidanze S,Pratt JK,Liu D,Hasvold L,Uziel T,Lu X,Kohlhapp F,Fang G,Elmore SW,Rosenberg SH,McDaniel KF,Katidoi
10.1158/0008-5472.CAN-16-1793subject
Has Abstractpub_date
2017-06-01 00:00:00pages
2976-2989issue
11eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-16-1793journal_volume
77pub_type
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