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Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies

Abstract

The 'hallmarks of cancer' are generally accepted as a set of genetic and epigenetic alterations that a normal cell must accrue to transform into a fully malignant cancer. It follows that therapies designed to counter these alterations might be effective as anti-cancer strategies. Over the past 30 years, research on the BCL-2-regulated apoptotic pathway has led to the development of small-molecule compounds, known as 'BH3-mimetics', that bind to pro-survival BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and, specifically, its roles in cancer development and therapy.

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Figure 1: Timeline of key discoveries.
Figure 2: The BCL-2 family comprises three subsets of interacting family members.
Figure 3: BCL-2-regulated apoptosis signalling.
Figure 4: Mechanisms of BCL-2 family deregulation in human cancer.

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Acknowledgements

The authors thank J. M. Adams, S. Cory, P. Bouillet, D. Huang, M. Herold, D. Gray, G. Lessene, P. Colman, R. Kluck, G. Dewson, B. Kile, A. Roberts, L. A. O'Reilly, G. Kelly, C. Vandenberg, B. Aubrey, F. Ke, A. Janic, L. Valente, S. Alvarez-Diaz, A. Kueh, J. Low, L. Rohrbeck, R. Schenk, M. Brennan, R. Salvamoser and B. Yang for insightful discussions. Work in the authors' laboratories is supported by grants and fellowships from the Cancer Council of Victoria (postdoctoral fellowship to S.G., a Sydney Parker Smith postdoctoral research fellowship to A.R.D.D. and grant in aid 1044722 to D.L.V.); a Lady Tata Memorial Trust postdoctoral award (to S.G.); a Leukaemia Foundation Australia postdoctoral fellowship (to S.G.); a Cure Brain Cancer Innovation Grant (to A.S. and S.G.); the Australian National Health and Medical Research Council (NHMRC) (program grant #1016701and NHMRC SPRF fellowships 1020363 (to A.S.) and 1020136 (to D.L.V.)); the Leukemia and Lymphoma Society (SCOR grant #7001-13); the Estate of Anthony (Toni) Redstone OAM; Melbourne International Research Scholarship (University of Melbourne, to S.G.); Melbourne International Fee Remission Scholarship (University of Melbourne, to S.G.); Australian Postgraduate Award (to A.R.D.D.) and Cancer Therapeutics CRC top-up scholarship (to S.G. and A.R.D.D). Work in the authors' laboratories is made possible by operational infrastructure grants through the Australian Government Independent Research Institutes Infrastructure Support (IRISS) and the Victorian State Government OIS.

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A.R.D.D., S.G., A.S. and D.L.V. are employed by the Walter and Eliza Hall Institute. The Walter and Eliza Hall Institute receives milestone payments from Genentech Inc. and AbbVie for the development of BH3-mimetic drugs ABT-199 and ABT-263 for cancer therapy.

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Delbridge, A., Grabow, S., Strasser, A. et al. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 16, 99–109 (2016). https://doi.org/10.1038/nrc.2015.17

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