LINC00511 drives osimertinib resistance in LUAD via PERK kinase: A clinical biomarker with enzymatic therapeutic potential.
TL;DR
These findings provide clinical evidence for the early diagnosis and risk stratification of Osimertinib resistance, and suggest that targeting the LINC00511-PERK-Nrf2 axis may become a novel therapeutic strategy for restoring drug sensitivity.
Abstract
Background
Osimertinib resistance is a major challenge in the treatment of EGFR-mutated lung adenocarcinoma (LUAD), and the role of LINC00511 in this process remains unclear.
Methods
We analyzed LINC00511 expression, patient prognosis, and its correlation with EIF2AK3 (encoding PERK) in LUAD using the GEPIA2 database, and further validated its circulating levels in patient peripheral blood by RT-qPCR. In vitro experiments, we constructed osimertinib-resistant H1650-OS and H1975-OS cell lines and regulated the expression of LINC00511 using genetic means. We evaluated the effects on resistance through functional experiments and used Western blot to detect PERK/Nrf2 and ER stress (ERS)-related proteins. Finally, we established a xenograft model to validate the in vitro findings in vivo.
Results
The results showed that elevated LINC00511 levels in patients with osimertinib resistance, and positively correlated with PERK. Knockdown of LINC00511 could block the activation of the PERK/Nrf2 axis, inducing ERS. In vivo experiments confirmed that silencing LINC00511 enhances the inhibitory effect of osimertinib on osimertinib-resistant LUAD. Mechanistically, LINC00511 inhibits ERS through the PERK-Nrf2 pathway, thereby driving resistance.
Conclusion
These findings provide clinical evidence for the early diagnosis and risk stratification of Osimertinib resistance, and suggest that targeting the LINC00511-PERK-Nrf2 axis may become a novel therapeutic strategy for restoring drug sensitivity, offering potential targets for the development of intelligent diagnostic and therapeutic nanomaterials.