Targeting TROP2 in drug‑tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non‑small‑cell lung cancer
Targeting TROP2 in drug‑tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non‑small‑cell lung cancer
Drug‑tolerant persister (DTP) cells are a key driver of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR‑mutant non‑small‑cell lung cancer (NSCLC). Comprehensive analysis revealed that TROP2 is dynamically upregulated during TKI‑induced DTP formation and contributes to DTP maintenance. Mechanistically, the transcriptional repressor c‑Myc is down‑regulated by TKI‑mediated MAPK inhibition, leading to TROP2 up‑regulation. Importantly, combining the TROP2‑targeting antibody‑drug conjugate sacituzumab tirutamic (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 in patients with advanced EGFR‑mutant NSCLC has shown preliminary efficacy, supporting the clinical development of TROP2‑ADC combined with EGFR‑TKI as a strategy to delay resistance and improve outcomes.
DTP cells mediate early resistance to EGFR TKIs in NSCLC, limiting treatment durability. Targeting TROP2, a vulnerability specifically up‑regulated in DTPs, with a potent ADC in combination with EGFR‑TKIs offers a novel therapeutic avenue to delay resistance and prolong patient benefit.
Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.
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