title: The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism.
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 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. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, 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.
authors.affiliation: 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;
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Anderson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.affiliation: Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia; Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and.
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.affiliation: Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia; Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and.
authors.forename: Constantine
authors.initials: C
authors.lastname: Tam
authors.affiliation: AbbVie, North Chicago, IL.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Joshua
authors.initials: J
authors.lastname: Fein
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Lijian
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and.
authors.forename: David
authors.initials: D
authors.lastname: Westerman
authors.affiliation: Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: Eric G
authors.initials: EG
authors.lastname: Si
authors.affiliation: Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Majewski
authors.affiliation: Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: David
authors.initials: D
authors.lastname: Segal
authors.affiliation: AbbVie, North Chicago, IL.
authors.forename: Sari L
authors.initials: SL
authors.lastname: Heitner Enschede
authors.affiliation: 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;
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: 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;
authors.forename: Andrew W
authors.identifier: 0000-0002-7341-5720
authors.initials: AW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C579720:venetoclax