Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2 + ) breast cancer. Drug-tolerant persisters (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2 + breast cancer cells cycle stochastically through a pre-DTP state, characterized by a G 0 -like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2 + breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3 , leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. SIGNIFICANCE: DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells (pre-DTPs) that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities.

Automated summary

Resistance to targeted therapies in HER2-positive breast cancer is often attributed to the presence of drug-tolerant persisters (DTPs). This study reveals that HER2 TKI treatment leads to the emergence of DTPs with different transcriptomes, and these DTPs are originated from pre-DTP cells that cycle stochastically. The findings provide insights into the ontogeny of DTPs and potential vulnerabilities for therapeutic targeting.