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

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Resistance to targeted therapies like tyrosine kinase inhibitors (TKIs) is a major challenge in HER2-positive breast cancer.
• Drug-tolerant persisters (DTPs), a subpopulation of cancer cells surviving through nongenetic mechanisms, are implicated in therapy resistance but poorly understood in this context.

Purpose of the Study:

• To characterize DTPs in HER2-positive breast cancer following HER2 TKI exposure.
• To elucidate the ontogeny and transcriptional states of DTPs.
• To identify potential vulnerabilities of DTPs for therapeutic targeting.

Main Methods:

• Lentiviral barcoding and single-cell RNA sequencing to track cell states.
• Trajectory analysis and cell sorting to identify precursor cells.
• Biochemical experiments to investigate survival mechanisms.

Main Results:

• HER2 TKIs induce DTPs with either luminal-like or mesenchymal-like transcriptomes.
• Pre-DTP cells, characterized by G0-like signatures and diapause/senescence genes, preferentially give rise to DTPs.
• Luminal-like DTPs rely on estrogen receptor-dependent SGK3 induction for survival, rewiring the PI3K/AKT/mTORC1 pathway for AKT-independent mTORC1 activation.
• Similar cell transcriptomes are found in HER2+ tumors and correlate with poor TKI response.

Conclusions:

• DTPs in HER2+ breast cancer arise from stochastic pre-DTP states and adopt distinct transcriptional programs.
• Understanding DTP ontogeny and survival mechanisms reveals potential therapeutic vulnerabilities.
• Targeting estrogen receptor signaling or downstream pathways may overcome TKI resistance mediated by luminal-like DTPs.