Dual-Targeting TrxR-EGFR Alkynyl-Au(I) Gefitinib Complex Induces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradation of GPX4

Gefitinib exhibits significant clinical
efficacy in patients
with
non-small cell lung cancer (NSCLC) harboring epidermal growth factor
receptor (EGFR) sensitive mutations. However, its efficacy is severely
limited by acquired resistance. Herein, we designed and synthesized
a series of dual-targeting thioredoxin reductase (TrxR)-EGFR gold
complexes by attaching a gold ligand to the parent structure of gefitinib,
4-anilinoquinazoline. Among them, L1Au2 exhibited significant
activity against both gefitinib-sensitive and resistant lung cancers,
effectively inhibiting tumor proliferation and promoting apoptosis.
Mechanistically, L1Au2 effectively inhibits TrxR and
EGFR both in vitro and in vivo. Additionally, L1Au2 promotes
the degradation of GPX4 protein via autophagolysosomal and proteasomal
pathways, leading to ferroptosis. Notably, L1Au2 also
induces endoplasmic reticulum stress (ERS) and triggers immunogenic
cell death (ICD). In conclusion, this study provides an innovative
strategy for overcoming gefitinib resistance in lung cancer by utilizing
dual-targeting TrxR-EGFR alkynyl-Au(I) gefitinib derivatives, thereby
offering a new approach for treating gefitinib-resistant lung cancer.