Ivacaftor,a CFTR potentiator,synergizes with osimertinib against acquired resistance to osimertinib in NSCLC by regulating CFTR-PTEN-AKT axis  

作　　者：Yue-kang Li Fu-jing Ge Xiang-ning Liu Chen-ming Zeng Mei-jia Qian Yong-hao Li Ming-ming Zheng Jing-jing Qu Liang-jie Fang Jin-jian Lu Bo Yang Qiao-jun He Jian-ya Zhou Hong Zhu 

机构地区：[1]Department of Respiratory Disease,Thoracic Disease Center,The First Affiliated Hospital,College of Medicine,Zhejiang University,Hangzhou,310003,China [2]Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China [3]The Clinical Research Center for Respiratory Diseases of Zhejiang Province,Hangzhou,310003,China [4]Engineering Research Center of Innovative Anticancer Drugs,Ministry of Education,Hangzhou,310058,China [5]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao,999078,China [6]School of Medicine,Hangzhou City University,Hangzhou,310015,China [7]Innovation Institute for Artificial Intelligence in Medicine,Zhejiang University,Hangzhou,310058,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期1045-1057,共13页中国药理学报(英文版)

基　　金：supported by Zhejiang Major R&D programs(2021C03042);Key R&D Program of Zhejiang Respiratory Disease(2023C03069);Zhejiang Provincial Clinical Research Center for Respiratory Disease(2022E50005).

摘　　要：Osimertinib,a third-generation epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI),has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer(NSCLC).However,inevitable acquired resistance to osimertinib limits its clinical utility,and there is a lack of effective countermeasures.Here,we established osimertinib-resistant cell lines and performed drug library screening.This screening identified ivacaftor,a cystic fibrosis transmembrane conductance regulator(CFTR)potentiator,as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo.Mechanistically,ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN,subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth.In summary,our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis.Furthermore,ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients.

关 键 词：NSCLC osimertinib acquired resistance ivacaftor CFTR 

分 类 号：R734.2[医药卫生—肿瘤]