Miao Zhimin, Sha Zhou, He Jianzhong, Liang Yongkai, Tan Lihua, Zhao Yuxin, Cui Xiaobing, Zhong Jinmiao, Zhong Ruting, Liang Huijun, Yue Wendi, Qiu Boyang, Gao Yunzhen, Zhang Lan, Teng Zixin, He Zeen, Chen Li, Xiao Rufei, Pei Xiaofeng, He Chengwei
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR 999078, China.
Department of Thoracic Oncology, The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Drug Resist Updat. 2025 Nov;83:101245. doi: 10.1016/j.drup.2025.101245. Epub 2025 Apr 23.
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.
奥希替尼（OSI）在表皮生长因子受体（EGFR）突变型肺癌中的治疗效果最终受到获得性耐药的限制，而其耐药机制仍知之甚少。在此，我们鉴定出一种新型长链非编码RNA，即LRTOR，它是非小细胞肺癌（NSCLC）中OSI耐药的关键驱动因素。临床数据表明，LRTOR表达升高与OSI耐药患者的不良预后相关。在功能上，LRTOR在体外和体内均能促进肿瘤生长并赋予OSI耐药性。从机制上讲，LRTOR可保护Yes相关蛋白（YAP）免受大肿瘤抑制因子1（LATS）介导的丝氨酸127和丝氨酸381位点的磷酸化作用，从而防止其经蛋白酶体降解。此外，LRTOR促进YAP与钾通道相互作用蛋白1（KCMF1）之间的相互作用，促进K63连接的泛素化、YAP的核转位以及YAP/TEAD1转录复合物的形成，进而触发LRTOR的转录，建立一个正反馈环，放大YAP的致癌信号并因此诱导OSI耐药。如在患者来源的类器官异种移植模型中所示，通过小干扰RNA（siRNA）耗尽LRTOR可恢复耐药肿瘤对OSI的敏感性。我们的研究结果揭示了LRTOR是NSCLC中OSI耐药的核心调节因子，并提出它是克服EGFR突变型肺癌中获得性OSI耐药的一个有前景的治疗和预后靶点。
