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In samples from patients with EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody\u2013drug conjugates (ADC). We confirmed these findings across multiple EGFR-mutated NSCLC cell line and patient-derived xenograft models treated with osimertinib in vivo. Treatment with the TROP2 ADC sacituzumab govitecan at the time of osimertinib-induced minimal residual disease only modestly delayed tumor recurrence in vivo, whereas a single infusion of sacituzumab-based TROP2-directed chimeric antigen receptor (CAR) T cells significantly prolonged relapse-free survival, with evidence of cure. These data highlight the potential of engineering TROP2 CAR T-cell therapy to eliminate EGFR DTPs in patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>We provide a rationale for targeting TROP2 in EGFR-mutated NSCLC DTPs. In contrast to TROP2 ADC therapy, targeting of TROP2 with CAR-T cells can eliminate osimertinib-induced DTPs in vivo, revealing the promise of developing novel TROP2-based CAR-T cells to promote durable response and prevent disease relapse in patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1515","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T12:34:47Z","timestamp":1754397287000},"page":"2235-2250","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Eradicating Drug-tolerant Persister Cells in\n                    <i>EGFR-<\/i>\n                    Mutated Non\u2013Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3610-1316","authenticated-orcid":false,"given":"Simon","family":"Baldacci","sequence":"first","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."},{"name":"2Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6283-0267","authenticated-orcid":false,"given":"Elliott J.","family":"Brea","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."},{"name":"2Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-6341","authenticated-orcid":false,"given":"Francesco","family":"Facchinetti","sequence":"additional","affiliation":[{"name":"1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."},{"name":"2Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5268-6986","authenticated-orcid":false,"given":"Zhaorong","family":"Li","sequence":"additional","affiliation":[{"name":"3Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5511-2825","authenticated-orcid":false,"given":"Kenneth","family":"Ngo","sequence":"additional","affiliation":[{"name":"4Belfer Center for Applied Cancer Science, 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