CircSPINT2 Confers Sensitivity to Osimertinib via hsa-miR-1296-3p/RBP1 Axis and Inhibits NSCLC Progression

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Resistance to osimertinib, a 3rd generation EGFR-TKI, develops within 12 months in patients with EGFR T790M mutation. This study used RNA-seq to identify circular RNAs (circRNAs) regulating osimertinib resistance in LUAD. We identified circSPINT2 as downregulated in osimertinib-resistant cell lines (OR3, OR4, OR6, HOsR) compared to parental H1975 cells. circSPINT2 enhances osimertinib sensitivity by inducing apoptosis via the hsa-miR-1296-3p/RBP1 axis. circSPINT2 is proposed as a non-invasive biomarker for monitoring osimertinib resistance in LUAD. Overall design: RNA-seq was performed on three osimertinib-resistant clones (OR3, OR4, OR6) derived from the H1975 NSCLC cell line and the parental H1975 cell line to profile circRNA expression. An independent osimertinib-resistant cell line (HOsR) was used for validation. Differential expression was validated by RT-qPCR for selected circRNAs.