Abstract
Acquisition of resistance to anti-cancer therapies is a multistep process initiated by the survival of drug-tolerant persister cells. Accessibility of drug-tolerant persister cells in patients is limited, which has hindered understanding the mechanisms driving their emergence. Here, using multiple patient-derived models to isolate persister cells, we showed that these cells are transcriptionally plastic in vivo and return to a common treatment naïve-like state upon relapse, regardless of treatment. Hallmarks of the persister state in TNBC across treatment modalities included high expression of basal keratins together with activation of stress response and inflammation pathways. These hallmarks were also activated in HER2+ breast and lung cancer cells in response to targeted therapies. Analysis of gene regulatory networks identified AP-1, NF-κB and IRF/STAT as the key drivers of this hallmark persister state. Functionally, FOSL1, an AP-1 member, drove cells to the persister state by binding enhancers and reprogramming the transcriptome of cancer cells. On the contrary, cancer cells without FOSL1 had a decreased ability to reach the persister state. By defining hallmarks of TNBC persistence on multiple therapies, this study provides a resource to design effective combination therapeutic strategies that limit resistance.