DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence un mécanisme par lequel le facteur de fragmentation de l'ADN B (DNase activée par la caspase) favorise, lors d'une thérapie ciblant des oncogènes, la reprise de la croissance des cellules cancéreuses persistantes via la suppression transcriptionnelle des gènes stimulés par l'interféron de type I
Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment.
Nature Cell Biology , article en libre accès, 2025