Eradicating Drug Tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T cellular therapy

Abstract EGFR tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes for EGFR-mutated non-small cell lung cancer (NSCLC) patients, but relapse frequently occurs due to 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-TKIs in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody drug conjugates (ADCs). 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 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.