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Decoding and unlocking the BCL-2 dependency of cancer cells

Nature Reviews Cancer volume 13, pages 455–465 (2013)Cite this article

Subjects

Key Points

  • The balance between pro- and anti-apoptotic activities of BCL-2 family members is tipped towards survival in many cancer cells, thus allowing them to survive various stressful environments, tumour stress phenotypes and/or oncogene-induced death signals.

  • As death signals may persist during tumour progression, cancer cells may be addicted to these survival mechanisms and be in a state of dependence on 'BCL-2-like' (BCL-2L) anti-apoptotic proteins.

  • Survival of 'BCL-2L-dependent' cancer cells relies on the maintenance of protein–protein complexes in which the BH3 domain of some pro-apoptotic BCL-2 family members engages a hydrophobic groove at the surface of anti-apoptotic BCL-2L proteins.

  • Structural characterization of the BH3-binding interface of anti-apoptotic BCL-2L proteins has led to the identification of small-molecule BH3 mimetics that disrupt key interactions and promote cancer cell apoptosis by on-target effects.

  • A dual BCL-2 and BCL-XL inhibitor and a specific BCL-2 inhibitor have shown clinical activity in haematological malignancies. The dual inhibitor induces dose-limiting thrombocytopenia owing to BCL-XL inhibition.

  • Finely-tuned inhibition of BCL-XL and of MCL1 in cancer cells by new and selective drugs remains a challenge and a necessity.

  • Understanding the exact effects of inhibitors on endogenous (membrane-localized) complexes, identifying predictive biomarkers for drug efficacy and circumscribing the global biological effects of these compounds is also required.

Abstract

Cancer cells are subject to many apoptotic stimuli that would kill them were it not for compensatory prosurvival alterations. BCL-2-like (BCL-2L) proteins contribute to such aberrant behaviour by engaging a network of interactions that is potent at promoting survival but that is also fragile: inhibition of a restricted number of interactions may suffice to trigger cancer cell death. Currently available and novel compounds that inhibit these interactions could be efficient therapeutic agents if this phenotype of BCL-2L dependence was better understood at a molecular, cellular and systems level and if it could be diagnosed by relevant biomarkers.

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Figure 1: Regulation of mitochondrial outer membrane permeabilization and cell survival by interacting BCL-2 family members.
Figure 2: Regulation of BCL-2L proteins by oncogenic signalling.
Figure 3: BCL-2L protein dependence as an output of complex, interconnected oncogenic signalling networks.
Figure 4: Transcriptional, post-transcriptional and post-translational regulation of MCL1 in cancer cells.

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Acknowledgements

We apologize for our inability to cite all the contributing primary literature owing to space constraints. We wish to thank D. Andrews, J. Hickman, D. Huang, A. Letai, J.-C. Martinou, and A. Strasser for fruitful discussion, and all members of our laboratories for their constant support and seemingly unbreakable enthusiasm. P.J. thanks his friends from Bénodet (Finistère, France) for their support and warm welcome, especially during the initial stages of writing this manuscript.

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Authors and Affiliations

  1. Team 8 “Cell survival and tumor escape in breast cancer”, UMR 892 INSERM / 6299 CNRS / Université de Nantes, Institut de Recherche Thérapeutique de l'Université de Nantes, 8 quai Moncousu, BP 70721, NANTES Cedex, 1, 44007, France

    Philippe Juin, Fabien Gautier & Mario Campone

  2. Institut de Cancérologie de l'Ouest (ICO), Centre de Lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, Saint Herblain-Nantes cedex, 44805, France

    Philippe Juin, Fabien Gautier & Mario Campone

  3. Institut de Recherche Servier, Cancer Research and Drug Discovery, 125 Chemin de Ronde, Croissy sur Seine, 78290, France

    Olivier Geneste & Stéphane Depil

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  1. Philippe Juin
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Correspondence to Philippe Juin.

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FURTHER INFORMATION

BCL-2 family database

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Glossary

Apoptotic threshold

The amount of stress that has to be imposed on a given cell population to trigger apoptotic death.

Caspase activation

A caspase multimerization-induced conformational change leading to auto-catalytic processing and activation of caspases, which are a family of cysteine active proteases.

BH3 mimetics

Compounds that interfere with the prosurvival function of anti-apoptotic BCL-2 family members by interacting with their BH3-binding groove and competing with (some) pro-apoptotic BCL-2 members for binding.

Stapled peptide

A peptide in which helicity is stabilized by the introduction of an intramolecular hydrocarbon linker between crucial residues. This modification protects the peptide from proteolytic degradation and enhances its ability to cross cell membranes.

Oncogene addiction

A status in which a cancer cell seems to have acquired an exquisite dependence on an activated oncogene for proliferation or survival.

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Juin, P., Geneste, O., Gautier, F. et al. Decoding and unlocking the BCL-2 dependency of cancer cells. Nat Rev Cancer 13, 455–465 (2013). https://doi.org/10.1038/nrc3538

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