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What can we learn from mice lacking pro-survival BCL-2 proteins to advance BH3 mimetic drugs for cancer therapy?

Cell Death & Differentiation volume 29, pages 1079–1093 (2022)Cite this article

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Abstract

In many human cancers the control of apoptosis is dysregulated, for instance as a result of the overexpression of pro-survival BCL-2 proteins. This promotes tumorigenesis by protecting nascent neoplastic cells from stress and renders malignant cells resistant to anti-cancer agents. Therefore, several BH3 mimetic drugs targeting distinct pro-survival proteins have been developed. The BCL-2 inhibitor Venetoclax/ABT-199, has been approved for treatment of certain blood cancers and tens of thousands of patients have already been treated effectively with this drug. To advance the clinical development of MCL-1 and BCL-XL inhibitors, a more detailed understanding of their distinct and overlapping roles in the survival of malignant as well as non-transformed cells in healthy tissues is required. Here, we discuss similarities and differences in pro-survival BCL-2 protein structure, subcellular localisation and binding affinities to the pro-apoptotic BCL-2 family members. We summarise the findings from gene-targeting studies in mice to discuss the specific roles of distinct pro-survival BCL-2 family members during embryogenesis and the survival of non-transformed cells in healthy tissues in adults. Finally, we elaborate how these findings align with or differ from the observations from the clinical development and use of BH3 mimetic drugs targeting different pro-survival BCL-2 proteins.

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Fig. 1: The regulation of the mitochondrial apoptotic pathway by pro-survival BCL-2 proteins.
Fig. 2: Subcellular localisation of the pro-survival BCL-2 proteins.
Fig. 3: Expression profile of pro-survival BCL-2 family members in solid tissues.
Fig. 4: mRNA expression profile of pro-survival BCL-2 family members in haematopoietic cell populations.

Data availability

There are no primary data presented in this review article.

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Acknowledgements

We thank Dr Marco Herold for discussion of the data that are reviewed here. We thank Dr Andrew Roberts for sharing his experience from clinical treatment of patients with Venetoclax and Dr David Huang for sharing his insights into the stability of BAX protein.

Funding

The work by the authors was supported by grants and fellowships from the Deutsche Krebshilfe (Dr Mildred Scheel post-doctoral fellowship to KB), the National Health and Medical Research Council (Program Grant #1113133, Fellowship 1116937, Investigator Grant #2007887, Synergy Grant #2010275; all to AS) and the Leukaemia and Lymphoma Society (SCOR Grant #7015-18 to AS).

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Vic, Australia

    Kerstin Brinkmann, Ashley P. Ng, Carolyn A. de Graaf & Andreas Strasser

  2. The Department of Medical Biology, University of Melbourne, Melbourne, Vic, Australia

    Kerstin Brinkmann, Ashley P. Ng, Carolyn A. de Graaf & Andreas Strasser

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  1. Kerstin Brinkmann
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  2. Ashley P. Ng
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  4. Andreas Strasser
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Contributions

KB and AS discussed and interpreted all primary research papers mentioned in this review. KB wrote the manuscript with the help of AS. KB designed Figs. 1 and 2. CdG analysed publicly available gene expression data and designed Figs. 3 and 4. AN and KB produced Table 4 and AN described the findings about on-target toxicities of BH3 mimetic drugs in patients and pre-clinical tests in mice.

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Correspondence to Kerstin Brinkmann or Andreas Strasser.

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Competing interests

All authors are employees of The Walter and Eliza Hall Institute (WEHI). WEHI receives royalties and milestone payments from the sale of Venetoclax. AS has received funding for his research from Servier and has served on a strategic advisory board from Servier.

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Brinkmann, K., Ng, A.P., de Graaf, C.A. et al. What can we learn from mice lacking pro-survival BCL-2 proteins to advance BH3 mimetic drugs for cancer therapy?. Cell Death Differ 29, 1079–1093 (2022). https://doi.org/10.1038/s41418-022-00987-0

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