Blood 2016 06 11;127(25):3215-24. Epub 2016 Apr 11.
Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia; Department of Clinical Hematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Parkville, VIC, Australia;
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 1 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. Read More