Apoptotic DNase DFFB mediates cancer persister cell adaptation to drug stress and regrowth

Tumours frequently acquire drug resistance resulting in disease relapse and patient mortality. Therapeutic approaches to treat drug resistant tumours are complicated by continual tumour evolution and multiple resistance mechanisms. Rather than treating resistance after it emerges, it may possible to prevent it by inhibiting the adaptive processes which initiate resistance but these are poorly understood. Here we report that drug tolerant cancer persister cells, which constitute residual disease and can seed relapse, undergo chronic sublethal apoptotic stress which paradoxically drives tumour adaptation and regrowth. Within persister cells, drug stress induces Type I interferon signaling which is growth suppressive. However, sublethal apoptotic signaling in persister cells activates apoptotic DNase DNA Fragmentation Factor B (DFFB, also known as Caspase-activated DNase, CAD, and DFF40) which, through induction of stress response factor ATF3, suppresses interferon-stimulated genes to allow persister cells to escape growth arrest and regrow. Consequently, DFFB deficient persister cells exhibit elevated interferon signaling which prevents their regrowth. In addition, DFFB mediates DNA damage and mutagenesis which can promote tumour evolution. These findings indicate sublethal apoptotic signaling facilitates tumour adaptation to drug treatment and reveal DFFB as a potential therapeutic target to prevent acquired drug resistance.