TEMPORARY REMOVAL: Long non-coding RNA LRTOR drives osimertinib resistance in non-small cell lung cancer by boosting YAP positive feedback loop

• DOI: 10.1016/j.drup.2025.101245
• Publication Date: 2025-04-23T23:28:07Z
• Authors: Zhimin Miao; Zhou Sha; Jianzhong He; Yongkai Liang; Lihua Tan; Yuxin Zhao; Xiaobing Cui; Jinmiao Zhong; Ruting Zhong; Huijun Liang; Wendi Yue; Boyang Qiu; Yunzhen Gao; Lan Zhang; Zixin Teng; Zeen He; Li Chen; Rufei Xiao; Xiaofeng Pei; Chengwei He
• Keywords: Osimertinib; Boosting; Positive feedback

The therapeutic efficacy of osimertinib (OSI) in EGFR-mutant lung cancer is ultimately limited by the onset acquired resistance, which mechanisms remain poorly understood. Here, we identify a novel long non-coding RNA, LRTOR, as key driver OSI resistance non-small cell (NSCLC). Clinical data indicate that elevated LRTOR expression correlates with poor prognosis OSI-resistant patients. Functionally, promotes tumor growth and confers both vitro vivo. Mechanistically, shields YAP from LATS-mediated phosphorylation at Ser127 Ser381, preventing its proteasomal degradation. Furthermore, facilitates interaction between KCMF1, promoting K63-linked ubiquitination, nuclear translocation YAP, formation YAP/TEAD1 transcriptional complex, turn triggers transcription establishing positive feedback loop amplifies oncogenic signaling consequently induces resistance. depletion siRNA restores sensitivity resistant tumors, demonstrated patient-derived organoid xenograft models. Our findings unveil central regulator NSCLC propose it promising prognostic target for overcoming cancer.