Eradicating Drug-Tolerant Persister Cells in EGFR-Mutated Non–Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy
Menée à l'aide de lignées cellulaires, de xénogreffes et d'échantillons tumoraux issus de patients atteints d'un cancer du poumon non à petites cellules avec mutation du gène EGFR, cette étude met en évidence l'intérêt de lymphocytes CAR-T ciblant la protéine TROP2 pour éradiquer les cellules cancéreuses résistantes aux anticancéreux
EGFR tyrosine kinase inhibitors have dramatically improved outcomes for patients with EGFR-mutated non–small cell lung cancer (NSCLC), but relapse frequently occurs because of drug-tolerant persister (DTP) cells that can evolve and develop diverse mechanisms of drug resistance. 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–drug 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.
Cancer Discovery , résumé, 2025