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A major contributor to ET failure is the presence of ET-insensitive cell populations within tumors. Here, we developed an analytical pipeline to systematically identify and target these populations by integrating single-cell RNA sequencing of ER+ tumors from the FELINE clinical trial with functional validation in a panel of patient-derived xenograft organoid models. We found that ET-insensitive cells are detected in all tumors regardless of clinical response and exhibit higher transcriptional heterogeneity than ET-sensitive populations. Using our pipeline, we identified and validated new therapeutic options that target patient-specific and shared ET-insensitive populations. Our integrated workflow provides a robust platform for identifying and targeting ET-insensitive cells and offers a translational framework to develop precision medicine approaches to improve outcome in breast cancer patients.<\/jats:p>","DOI":"10.64898\/2026.09.10.750719","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:35:19Z","timestamp":1789565719000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrative pipeline to profile and target endocrine therapy-insensitive cell populations in ER+ breast cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7992-0162","authenticated-orcid":false,"given":"Svetlana E.","family":"Semina","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, 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