A new study has identified four distinct drug-tolerant cell states in triple-negative breast cancer (TNBC) that persist after neoadjuvant chemotherapy, offering fresh insight into treatment resistance and metastatic progression.
Researchers generated a high-resolution single-cell atlas using 129,433 cells from 14 patient-derived xenograft models of TNBC with residual disease. Using unsupervised clustering, they found four transcriptionally distinct cancer cell states linked to hypoxia, interferon signaling, chromosomal instability, and DNA damage pathways.
Two of these states, associated with hypoxia and interferon signaling, share features with drug-tolerant persister cells. Notably, the hypoxia-related populations showed no link to mutation status, suggesting resistance may be driven by epigenetic rather than genetic mechanisms.
Validation across independent TNBC cohorts confirmed these dysregulated pathways exist even in chemotherapy-naïve tumors and persist in distant metastatic disease. The findings suggest neoadjuvant chemotherapy may selectively enrich these resistant persister cells, contributing to recurrence or progression.
Functional experiments highlighted a potential therapeutic target: inhibition of the lysine demethylase KDM5B suppressed the emergence of drug-tolerant persister cells. Researchers conclude that epigenetically regulated, hypoxia-related persister cells represent important therapeutic targets in TNBC.