Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell lung cancer.

Abstract

Drug-tolerant persister (DTP) cells play a key role in the development of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Through comprehensive analyses, we identify that TROP2 is dynamically upregulated during TKI-induced DTP formation and functionally contributes to DTP maintenance. Mechanistically, c-Myc acts as a transcriptional repressor of TROP2, and TKI-mediated MAPK pathway inhibition reduces c-Myc levels, leading to TROP2 upregulation. Importantly, combining the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) with osimertinib effectively suppresses DTP emergence and delays tumor relapse in preclinical models. An ongoing phase 2 trial evaluating first-line sac-TMT plus osimertinib combination therapy in patients with advanced EGFR-mutant NSCLC shows preliminary efficacy. Together, our findings establish TROP2 as a therapeutically actionable vulnerability in DTP cells and support the clinical development of TROP2-ADC combined with EGFR-TKI as a first-line strategy to delay TKI resistance and improve outcomes in EGFR-mutant NSCLC.