EMP3 is upregulated upon epithelial-mesenchymal transition and contributes to EGFR-tyrosine kinase inhibitor resistance in lung adenocarcinoma.

Tyrosine kinase inhibitors (TKIs) are a class of therapies used to target specific genetic mutations such as epidermal growth factor receptor (EGFR) mutations in cancer treatment. This study investigates the function of epithelial membrane protein 3 (EMP3) in EGFR-TKI resistance in lung adenocarcinoma (LUAD). Human LUAD cells HCC827 and H1975 were exposed to different doses of osimertinib or erlotinib to generate TKI-resistant cell lines. These cells exhibited increased expression of EMP3. EMP3 overexpression in parental cells significantly increased TKI resistance, as well as promoted proliferation, migration, and stem cell characteristics. Epithelial-mesenchymal transition (EMT) is a major cause for EMP3 upregulation, as overexpression of ZEB1 increased EMP3 expression. By contrast, inhibition of the TGF/β signaling with LY2109761 reduced EMP3 expression in cells. In vivo, EMP3-overexpressing mouse 3LL cells exhibited strengthened tumorigenic activity in C57BL/6 mice in the presence of osimertinib treatment, accompanied by increased stem cell markers. Notably, the LY2109761 treatment reduced TKI resistance and diminished expansion, migration, and stemness in cancer cells induced by EMP3 overexpression. In conclusion, this study indicates that EMP3, upregulated upon EMT, contributes to EGFR-TKI resistance in LUAD cells.