Abstract

Exosomes serve as critical mediators in driving therapeutic resistance among tumor cells by delivering bioactive molecules, including circular RNAs (circRNAs). Through bioinformatics mining of public databases, we identified circ_0097112 as a circular RNA implicated in icotinib resistance in lung adenocarcinoma (LUAD). Our subsequent experiments revealed that circ_0097112 was specifically upregulated in EGFR-TKI-resistant cells and in their secreted exosomes. To elucidate the functional role of circ_0097112 in EGFR-TKI-resistant lung cancer cells, we conducted in vitro experiments demonstrating that circ_0097112 promotes proliferation and concomitantly suppresses apoptosis in LUAD cells. Confocal microscopy revealed that drug-resistant lung cancer cells encapsulate circ_0097112 within exosomal vesicles and horizontally transfer this cargo to drug-sensitive recipient cells, thereby conferring acquired resistance. To delineate the mechanistic basis by which circ_0097112 confers drug resistance, we integrated bioinformatic prediction with experimental validation, including RNA pull-down and RNA immunoprecipitation assays. Our findings demonstrated that circ_0097112 directly interacts with UPF1 protein to assemble a functional complex, thereby suppressing decay of oncogenic NRAS. This molecular event consequently activates downstream RAF/MAPK signaling, attenuating apoptosis while promoting cellular proliferation and drug resistance. Collectively, this study reveals the pivotal involvement of the circ_0097112/UPF1/NRAS axis in driving EGFR-TKI resistance in LUAD and offers a new theoretical basis for targeting circ_0097112 to reverse EGFR-TKI resistance.