Abstract
Apoptosis is a form of programmed cell death that is regulated by the balance between prosurvival and proapoptotic BCL-2 protein family members. Evasion of apoptosis is a hallmark of cancer that arises when this balance is tipped in favour of survival. One form of anticancer therapeutic, termed ‘BH3-mimetic drugs’, has been developed to directly activate the apoptosis machinery in malignant cells. These drugs bind to and inhibit specific prosurvival BCL-2 family proteins, thereby mimicking their interaction with the BH3 domains of proapoptotic BCL-2 family proteins. The BCL-2-specific inhibitor venetoclax is approved by the US Food and Drug Administration and many regulatory authorities worldwide for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia. BH3-mimetic drugs targeting other BCL-2 prosurvival proteins have been tested in preclinical models of cancer, and drugs targeting MCL-1 or BCL-XL have advanced into phase I clinical trials for certain cancers. As with all therapeutics, efficacy and tolerability need to be carefully balanced to achieve a therapeutic window whereby there is significant anticancer activity with an acceptable safety profile. In this Review, we outline the current state of BH3-mimetic drugs targeting various prosurvival BCL-2 family proteins and discuss emerging data regarding primary and acquired resistance to these agents and approaches that may overcome this. We highlight issues that need to be addressed to further advance the clinical application of BH3-mimetic drugs, both alone and in combination with additional anticancer agents (for example, standard chemotherapeutic drugs or inhibitors of oncogenic kinases), for improved responses in patients with cancer.
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Acknowledgements
The work by the authors was supported by fellowships and grants from the Australian National Health and Medical Research Council (NHMRC) (Program Grant GNT1113133 to A.S. and G.L., Research Fellowships GNT1117089 to G.L., GNT1079700 to P.E.C. and GNT1116937 to A.S., Project Grants GNT1143105 to A.S. and GNT1158137 to P.E.C., Investigator Grant GNT1177718 to M.A.A. and Ideas Grants GNT 2002618 and GNT2001201 to G.L.K. and GNT2001406 to P.E.C.), the Leukemia & Lymphoma Society of America (Specialized Center of Research Program grant no. 7015-18 to A.S., G.L.K. and G.L.), the Victorian Cancer Agency (MCRF fellowship 17028 to G.L.K.), the estate of Anthony (Toni) Redstone OAM(A.S. and G.L.K.), the Craig Perkins Cancer Research Foundation (G.L.K.), the Jack Brockhoff Foundation (M.A.A.) and the Dyson Bequest (G.L.K.). Work in the laboratories of the authors was made possible through the Victorian State Government Operational Infrastructure Support Program and the Australian Government NHMRC Independent Research Institute Infrastructure Support Scheme. The authors acknowledge A. Wei for discussions, C. McLean for assistance with the preparation of this Review and E. Conti for drafting of figures.
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All authors researched data for the article. G.L.K. S.T.D. and A.S. contributed substantially to discussion of the content. All authors contributed to the writing of the article. S.T.D., A.S. and G.L.K. reviewed and/or edited the manuscript before submission.
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All authors are employees of the Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax. G.L., A.S. and G.L.K. have received research funding from Servier. M.A.A. receives honoraria from AbbVie, Janssen, Novartis and Beigene.
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Glossary
- Apoptosome
-
A multiprotein complex composed of the adaptor protein APAF1, cytochrome c (released from the intermitochondrial space after activation of BAX and BAK) and procaspase 9 that promotes activation of caspase 9; this complex activates the effector caspases, unleashing dismantling of the cells undergoing apoptosis.
- K i
-
Dissociation constant for the interaction of, for example, a drug binding to its protein target.
- Hypomethylating agents
-
(HMAs). Drugs used for cancer treatment that inhibit DNA methylation and thereby perturb epigenetic regulation in cells.
- Thrombocytopenia
-
A reduction in platelet count.
- Tumour lysis syndrome
-
(TLS). A condition that can be life-threatening that occurs when large numbers of tumour cells die within a short period, releasing their contents into the blood, which can cause stress to the kidneys.
- Uric acid-lowering agents
-
Drugs that reduce the levels of uric acid in the blood; this can prevent kidney damage during tumour lysis syndrome.
- Undetectable minimal residual disease
-
(uMRD). The absence of chronic lymphocytic leukaemia cells in a patient after therapy.
- Hypogammaglobulinaemia
-
Abnormally low levels of antibodies (immunoglobulins).
- Composite complete response
-
(CRc). State in which the original blood cell cancer no longer persists and the blood cell counts in a patient have been normalized.
- Lymphopenia
-
Abnormal reduction in lymphocyte count.
- Clinical benefit rate
-
The percentage of patients with advanced or metastatic cancer who have achieved complete remission, partial remission and stable disease owing to a therapeutic intervention in clinical trials of anticancer agents.
- Richter transformation
-
An uncommon clinicopathological condition observed in about 5–10% of patients with chronic lymphocytic leukaemia that refers to the development of aggressive lymphoma during the course of chronic lymphocytic leukaemia.
- Amplicon
-
A section of chromosomal DNA that has been amplified.
- Surface plasmon resonance
-
The resonant oscillation of conduction electrons at the interface between negative-permittivity and positive-permittivity material stimulated by incident light. It is the basis of many standard tools for measuring adsorption of material onto planar metal (typically gold or silver) surfaces and is the fundamental principle behind many colour-based biosensor applications.
- Antibody–drug conjugates
-
Highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific for surface antigens present on particular tumour cells with highly potent anticancer agents linked via a chemical linker.
- Dendrimer
-
A highly ordered, branched polymeric molecule.
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Diepstraten, S.T., Anderson, M.A., Czabotar, P.E. et al. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nat Rev Cancer 22, 45–64 (2022). https://doi.org/10.1038/s41568-021-00407-4
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DOI: https://doi.org/10.1038/s41568-021-00407-4
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