浙江大学朱虹等研究人员合作发现，一种CFTR增强剂ivacaftor通过调节CFTR-PTEN-AKT轴与奥希替尼协同作用，来对抗奥希替尼在非小细胞肺癌中的获得性耐药。2024年12月3日，《中国药理学报》在线发表了这一成果。

研究人员表示，奥希替尼是一种第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），在治疗EGFR突变型非小细胞肺癌（NSCLC）中已显示出显著的临床益处。然而，奥希替尼的获得性耐药性是其临床应用的一个限制，而且目前缺乏有效的对策。

研究人员建立了奥希替尼耐药的细胞系，并进行了药物库筛选。筛选结果发现，ivacaftor（一种囊性纤维化跨膜导管调节因子（CFTR）增强剂）能够在体外和体内，协同增强奥希替尼的抗肿瘤活性。

机制研究表明，ivacaftor促进了CFTR与PTEN在质膜上的共定位，从而促进了PTEN的功能，随后抑制了PI3K/AKT信号通路并抑制肿瘤生长。

总之，该研究表明，通过调节PTEN-AKT轴，激活CFTR能够增强奥希替尼的抗肿瘤活性。此外，ivacaftor和奥希替尼构成了一种潜在的联合策略，可用于治疗奥希替尼耐药的EGFR突变型NSCLC患者。

附：英文原文

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

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

Issue&Volume: 2024-12-03

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.

DOI: 10.1038/s41401-024-01427-0

Source: https://www.nature.com/articles/s41401-024-01427-0