Characterization of Drug-Tolerant Persister Cells in Triple-Negative Breast Cancer Identifies a Shared Persistence Program across Treatments and Patients.

Abstract

Acquisition of resistance to anticancer 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. In this study, 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 triple-negative breast cancer (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. Elucidation of the features of the drug-tolerant persister state in triple-negative breast cancer reveals shared programs across patients and treatments that offer opportunities to prevent persistence and delay tumor recurrence.