Identification of a shared drug-tolerant persister program in triple-negactive breast cancer across treatments and patients [scRNA-Seq]

Acquisition of resistance to anti-cancer therapies is a multistep process, which initiates with the survival of drug tolerant persister cells. Understanding the mechanisms driving the emergence of drug tolerant persister cells remains challenging, primarily because of their limited accessibility in patients. Here, using multiple patient-derived models to isolate persister cells, we show these cells are transcriptionally plastic in vivo and return to a common treatment-naïve like state upon relapse, regardless of the treatment they have been exposed to. We reveal hallmarks of the persister state in TNBC across treatment modalities: high expression of basal keratins together with activation of a stress response and inflammation pathways. HER2+ breast and lunger cancer cells also activate these hallmarks of drug tolerance in response to targeted therapies. Leveraging gene regulatory networks, we identify AP-1, NFKB and IRF/STAT as the key drivers of this hallmark persister state. As a proof of concept, we show that FOSL1 - an AP-1 member - is sufficient to drive cells to the persister state by binding enhancers and reprogramming the transcriptome of cancer cells. On the contrary, cancer cells without FOSL1 have a decreased ability to reach the persister state. By defining hallmarks of drug persistence to multiple therapies of the standard of care in TNBC, our study provides a resource to design novel combination therapeutic strategies to limit resistance. scRNAseq of HBCx39, HBCx95, HBCx172, HBCx221 and HBCx218 Patient Derived Xenograft (PDX) of Triple Negative Breast Cancer (TNBC) in response to chemotherapies (Capecitabine and Anthracyclines *************************************************************** Raw FASTQ files are not publicly available due to patient data privacy considerations. ***************************************************************