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

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

Journal article

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

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

Blood | Published : 2016

DOI: 10.1182/blood-2016-01-688796

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, venet..

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University of Melbourne Researchers

John Seymour Author

Constantine Tam Author

David Westerman Author

Ian Majewski Author

Grants

Awarded by National Institutes of Health

Funding Acknowledgements

This work was supported by AbbVie, in collaboration with Genentech/Roche. Venetoclax (ABT-199/GDC-0199) is being developed through collaboration between AbbVie and Genentech/Roche. M.A.A. was supported by a fellowship from the Webster bequest. Work in the labs of D.C.S.H. and A.W.R. was supported by scholarships, fellowships, and grants from the Australian National Health and Medical Research Council (research fellowships [A.W.R. and D.C.S.H.], program grants 1016647 and 1016701, and Independent Research Institutes Infrastructure Support Scheme grant 9000220); the Leukemia and Lymphoma Society (SCOR grants 7001-13); the Victorian Cancer Agency; the Cancer Council Victoria; the Australian Cancer Research Foundation; and a Victorian State Government Operational Infrastructure Support grant. This work was supported by a grant from the National Cancer Institute, National Institutes of Health (CA129974) (A.L.). M.S.D. is supported by an American Society of Clinical Oncology Career Development Award.