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

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

  • Acta Pharmacol Sin. 2024 Dec 3. doi: 10.1038/s41401-024-01427-0.
Yue-Kang Li 1 2 3 4,  Fu-Jing Ge 2 4,  Xiang-Ning Liu 2 4,  Chen-Ming Zeng 2 4,  Mei-Jia Qian 2 4,  Yong-Hao Li 2 4,  Ming-Ming Zheng 2 4,  Jing-Jing Qu 1 3,  Liang-Jie Fang 1 3,  Jin-Jian Lu 5,  Bo Yang 2 4 6,  Qiao-Jun He 2 4 7,  Jian-Ya Zhou 8 9,  Hong Zhu 10 11 12
Affiliations

Affiliations

  • 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.
  • 8 Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China. zhoujy@zju.edu.cn.
  • 9 The Clinical Research Center for Respiratory Diseases of Zhejiang Province, Hangzhou, 310003, China. zhoujy@zju.edu.cn.
  • 10 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. hongzhu@zju.edu.cn.
  • 11 Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, 310058, China. hongzhu@zju.edu.cn.
  • 12 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310058, China. hongzhu@zju.edu.cn.
PMID: 39627385 DOI: 10.1038/s41401-024-01427-0
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.

Keywords

CFTR; NSCLC; acquired resistance; ivacaftor; osimertinib.

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