Eradicating Drug-tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy.

Publication/Presentation Date

11-3-2025

Abstract

UNLABELLED: 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.

SIGNIFICANCE: 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.

Volume

15

Issue

11

First Page

2235

Last Page

2250

ISSN

2159-8290

Disciplines

Medicine and Health Sciences

PubMedID

40762432

Department(s)

Medical Education

Document Type

Article

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