Ivacaftor, a CFTR potentiator, synergizes with osimertinib against acquired resistance to osimertinib in NSCLC by regulating CFTR-PTEN-AKT axis
Yue-kang Li1,2,3,4,
Fu-jing Ge2,4,
Xiang-ning Liu2,4,
Chen-ming Zeng2,4,
Mei-jia Qian2,4,
Yong-hao Li2,4,
Ming-ming Zheng2,4,
Jing-jing Qu1,3,
Liang-jie Fang1,3,
Jin-jian Lu5,
Bo Yang2,4,6,
Qiao-jun He2,4,7,
Jian-ya Zhou1,3,
Hong Zhu2,4,7
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 Macau, 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
Correspondence to: Jian-ya Zhou: zhoujy@zju.edu.cn, Hong Zhu: hongzhu@zju.edu.cn,
DOI: 10.1038/s41401-024-01427-0
Received: 10 June 2024
Accepted: 11 November 2024
Advance online: 3 December 2024
Abstract
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.
