Nalini Devi VerusingamAliaksandr A. YarmishynMin-Long TsaiPing-Hsing TsaiYi-Chen ChenChih-Ling YehCheong Soon KengPo-Kuei HsuShih-Hwa Chiou0000-0002-1882-7757Alan Ong Han KiatMong-Lien Wang2025-09-242025-09-242025-0910.1016/j.omton.2025.201007https://dspace-cris.utar.edu.my/handle/123456789/11365Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Prolonged treatment of LUAD with 1st/2nd generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) promotes the emergence of secondary EGFR T790M mutation conferring resistance to these drugs. Patients who acquire EGFR T790M mutation respond to the 3rd generation EGFR-TKI osimertinib but develop resistance within 12 months. Circular RNAs (circRNAs) are notably associated with cancerogenesis, making them promising biomarkers or therapeutic targets. In this study, we aimed to identify circRNAs that regulate osimertinib resistance and elucidate the functions and mechanisms to reveal potential therapeutic targets and biomarkers for osimertinib-resistant LUAD. The analysis of circRNA transcriptome sequencing identified circSPINT2 to be downregulated in osimertinibresistant cell lines. The loss-/gain-of-function assays revealed that circSPINT2 sensitizes cells to osimertinib treatment by inducing apoptosis. Functionally, circSPINT2 enhanced the expression of RBP1 by sponging hsa-miR-1296-3p. Osimertinib-resistant xenograft tumor model was established by long-term osimertinib treatment, and the molecular and histologic analysis of subcutaneous xenograft tumors corroborated our in vitro findings. Conclusively, our study demonstrates that circSPINT2 possesses tumor-suppressive functions; the restoration of circSPINT2 expression level confers sensitivity to osimertinib treatment via miR-1296-3p/RBP1 axis. The secreted circSPINT2 may serve as a monitoring biomarker for osimertinib resistance status in LUAD.enCELL LUNG-CANCERCIRCULAR RNACRBP1 GENEEXPRESSIONRESISTANCEPROLIFERATIONMETHYLATIONMUTATIONSCARCINOMAINVASIONjournal-article