Long non-coding RNA LRTOR drives osimertinib resistance in non-small cell lung cancer by boosting YAP positive feedback loop
Zhimin Miao, Sha Zhou, Jianzhong He, Yongkai Liang, Lihua Tan, Yuxin Zhao, Xiaobing Cui, Jinmiao Zhong, Ruting Zhong, Huijun Liang, Wen Yue, Boyang Qiu, Yunzhen Gao, Lan Zhang, Zixin Teng, Zhonglian He, Su Chen, Rufei Xiao, Xiaofeng Pei, Chengwei He
Abstract
The therapeutic efficacy of osimertinib (OSI) in EGFR-mutant lung cancer is ultimately limited by the onset of acquired resistance, of which the mechanisms remain poorly understood. Here, we identify a novel long non-coding RNA, LRTOR, as a key driver of OSI resistance in non-small cell lung cancer (NSCLC). Clinical data indicate that elevated LRTOR expression correlates with poor prognosis in OSI-resistant patients. Functionally, LRTOR promotes tumor growth and confers OSI resistance both in vitro and in vivo. Mechanistically, LRTOR shields YAP from LATS-mediated phosphorylation at Ser127 and Ser381, preventing its proteasomal degradation. Furthermore, LRTOR facilitates the interaction between YAP and KCMF1, promoting K63-linked ubiquitination, nuclear translocation of YAP, and formation of the YAP/TEAD1 transcriptional complex, which in turn triggers the transcription of LRTOR, establishing a positive feedback loop that amplifies oncogenic signaling of YAP and consequently induces OSI resistance. LRTOR depletion by siRNA restores OSI sensitivity in resistant tumors, as demonstrated in patient-derived organoid xenograft models. Our findings unveil LRTOR as a central regulator of OSI resistance in NSCLC and propose it as a promising therapeutic and prognostic target for overcoming acquired OSI resistance in EGFR-mutant lung cancer.