Senescence, apoptosis and therapy — cutting the lifelines of cancer

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Abstract
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.