Repositioning of nonsedating antihistamine Ebastine for anti-lung adenocarcinoma based on EGFR/ERBB2 dual-targeting strategy

Lung adenocarcinoma is a highly fatal carcinoma worldwide with limited therapeutic options. We identified EGFR/ERBB2 as promising dual targets through integrative analysis of clinical data and TCGA database. Molecular docking and cytotoxicity screening of FDA-approved drugs identified Ebastine as a potent dual-targeting agent. Ebastine significantly inhibited NCI-H1975 cell viability (EGFR-mutant with high EGFR/ERBB2 expression), induced ROS elevation, decreased mitochondrial membrane integrity, and triggered apoptosis. Western blot revealed that Ebastine suppressed phosphorylation of EGFR, ERBB2, ERK1/2 and AKT. In xenograft models, Ebastine significantly inhibited NCI-H1975 tumor growth with no significant impact on body weight. Histopathological and immunohistochemical analyses showed reduced Ki67 expression and increased tumor cell apoptosis in Ebastine-treated tumors. Notably, Ebastine promoted macrophage infiltration and M1 polarization both in vivo and in vitro . Our findings establish Ebastine as a promising therapeutic candidate for EGFR/ERBB2-mutant lung adenocarcinoma through a unique dual-targeting approach that combines direct tumor cell inhibition with enhancement of anti-tumor immunity.