The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53 independent mechanism

Anderson, MA; Deng, J; Seymour, JF; Tam, C; Kim, SY; Fein, J; Yu, L; Brown, JR; Westerman, D; Si, EG; Majewski, IJ; Segal, D; Heitner Enschede, SL; Huang, DC; Davids, MS; Letai, A; Roberts, AW

Author(s): Anderson, MA; Deng, J; Seymour, JF; Tam, C; Kim, SY; Fein, J; Yu, L; Brown, JR; Westerman, D; Si, EG; Majewski, IJ; Segal, D; Heitner Enschede, SL; Huang, DC; Davids, MS; Letai, A; Roberts, AW;
Details: Publication Year 2016-04-11,Volume 127,Issue #25,Page 3215-24
Journal Title: Blood
Publication Type: Journal Article
Abstract: BCL2 blunts activation of the mitochondrial pathway to apoptosis and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase I first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within four hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20mg or 50mg dose in some patients. The extent of mitochondrial depolarisation by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, while the LC50derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p,TP53mutation and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients, and support further assessment of BH3 profiling as a predictive biomarker for this drug.
Publisher: ASH
Research Division(s): Cancer And Haematology
PubMed ID: 27069256
Link To PubMed Central Version: https://www-ncbi-nlm-nih-gov/pmc/articles/PMC4920022/
Publisher's Version: https://doi.org/10.1182/blood-2016-01-688796
NHMRC Grants: NHMRC/1016647, NHMRC/1016701,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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