biostudies-literatureChang CAGovernment of OntarioFoundation for the National Institutes of HealthNCI NIH HHSGouvernement du Canada | Canadian Institutes of Health ResearchNIGMS NIH HHSCIHRHHS | NIH | NCI | Basic Research Laboratory1022-1045https://www.ebi.ac.uk/biostudies/studies/S-EPMC8983469biostudies-literatureUnknown12(4)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 G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKCancer discoveryOntogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer.PMC8983469GM124446P01 CA229086P01CA229086R01 CA148761P30 CA016087R01 CA264933R01 GM124446Ontario Research Excellence FundMOP-142375R01 CA049152CA59152Ueberheide BSotiriou CNeel BGDeng JJiang SWong KKSkok JASingh ABrown KRSayad ADhabaria ATsirigos AMer ASMeyn PChang CAHeguy ANixon AMLAdams SMoffat JTang KHVenet DHaibe-Kains BKhodadadi-Jamayran AJen JfalseOntogeny 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 G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TK2022-01-01T00:00:00Z2022 Apr2026-05-31T02:12:24.101Z2025-02-19T01:21:32.728ZS-EPMC89834693491173310.1158/2159-8290.cd-20-126510.1158/2159-8290.CD-20-1265