Exosomes-Transferred lncRNA H19 Reverses Osimertinib Resistance by Upregulating PTEN via Sponging miR-148-3p in...

Objective: Osimertinib can selectively inhibit both epidermal growth factor receptor (EGFR) sensitizing and T790M gatekeeper mutations, and has shown remarkable therapeutic effects in patients with lung adenocarcinoma. However, almost all patients inevitably develop drug resistance. Herein, we sought to clarify the roles of exosomal lncRNA H19 in modulating osimertinib resistance, focusing on the PI3K-PTEN-Akt signaling axis. Methods: Functional assays, including cell viability assay, colony formation, cell apoptosis and xenograft mouse, employed in evaluate the effects of exosomal lncRNA H19 on cell growth and apoptosis. RNA quantitation and western blot were adopted to demonstrate the regulatory roles of exosomal lncRNA H19 in PI3K-PTEN-Akt signaling pathway. Immunofluorescence was applied to obverse the function and distribution of exosomes. Furthermore, dual-luciferase reporter analysis combined with RNA immunoprecipitation (RIP) was applied to verify the molecular interaction between lncRNA H19 and phosphatase and tensin homolog (PTEN). Results: LncRNA H19 exhibited obviously decreased expression in H1975R cells and their secreted exosomes. Overexpression of H19 enhances the cytotoxicity of osimertinib, inhibits the growth of H1975R cells, and promotes apoptosis. Conversely, H19 silencing promotes osimertinib resistance in H1975 cells and enhances the cell-resistant phenotype. Furthermore, exosome-transferred lncRNA H19 sponged miR-148-3p to augment PTEN expression, which in turn inactivated the PI3K-Akt signaling pathway and ultimately induced cell apoptosis. Conclusion: Exosome-encapsulated lncRNA H19 can be delivered to osimertinib-resistant H1975R cells, thereby reversing resistance through the miR-148-3p/PTEN/PI3K-Akt axis. Our results uncover a potential therapeutic approach to surmount osimertinib resistance in lung cancer.