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Senescence, apoptosis and therapy — cutting the lifelines of cancer

Key Points

  • Oncogene-driven hyperproliferation and failsafe defects are the key cellular insults that enable malignant growth.

  • Mitogenic oncogenes preferentially provoke either apoptosis or premature senescence as cellular counteraction, leading to malignancies that harbour failsafe defects as 'oncogenic signatures'.

  • The 'lifelines' of cancer reflect defects in cellular growth control that are essential for tumorigenesis, such as disrupted apoptosis or senescence.By contrast, not all the mutations that are acquired during tumour progression are required to maintain neoplastic growth.

  • DNA-damaging anticancer drugs recruit the cell's failsafe machinery to execute apoptosis or cellular senescence.Defects in stress-response programmes that are acquired during tumour formation can co-select for drug resistance — even prior to drug exposure.

  • Identifying therapeutic approaches to 'cut the lifelines of cancer' is an appealing concept.By contrast, utilization or restoration of drug effector programmes that are not targeted during tumour formation could be a more efficient alternative.

  • Large-scale genetic screens and physiological test systems that allow high-throughput functional genomics are needed to identify key defects in failsafe pathways and to validate their implication for drug responses and novel therapeutic interventions.

Abstract

Apoptosis and senescence are cellular failsafe programmes that counteract excessive mitogenic signalling from activated oncogenes. Cancellation of apoptosis or senescence is therefore a prerequisite for tumour formation, and the ability of the cancer cell to disrupt these processes can be considered its 'lifeline'. Ironically, the efficacy of anticancer agents also depends on the activation of apoptosis or an acutely inducible form of cellular senescence. Understanding how the 'lifelines' of the cancer cell interfere with treatment sensitivity is of crucial importance for developing safer and more effective treatment strategies.

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Figure 1: Oncogene action and failsafe reaction.
Figure 2: The lifelines of cancer.
Figure 3: Anticancer genes and drug effectors.
Figure 4: The roads to resistance.

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Acknowledgements

Research in the author's laboratory is supported by grants from the Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe. The author is a Special Fellow of the Leukemia & Lymphoma Society. He is grateful for stimulating discussions with B. Dörken, and critical comments to the manuscript by S. Lee.

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DATABASES

Cancer.gov

chronic myelogenous leukaemia

gastric lymphoma

Hodgkin's disease

LocusLink

ABL

AKT

BAX

BCL10

BCL2

BCL-XL

BCR

caspase-9

CDK4

CDKN2A

IκBα

LMYC

MDM2

MYC

NF-κB

p53

phosphatidylinositol 3-kinase

RAS

RB

WAF1

FURTHER INFORMATION

The Berns lab

Clemens Schmitt's lab

Scott Lowe's web page

Glossary

FAILSAFE PROGRAMMES

Stress-responsive, genetically encoded programmes that ultimately eliminate defective or inappropriately proliferating cells from the cell cycle to ensure cellular integrity.

CYTOSTASIS

An acute, stress-inducible, long-term cell-cycle arrest that displays characteristics of cellular senescence.

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Schmitt, C. Senescence, apoptosis and therapy — cutting the lifelines of cancer. Nat Rev Cancer 3, 286–295 (2003). https://doi.org/10.1038/nrc1044

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