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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48.
Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398:535–54.
Harrison PT, Vyse S, Huang PH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin Cancer Biol. 2020;61:167–79.
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378:113–25.
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41–50.
Tan CS, Kumarakulasinghe NB, Huang YQ, Ang YLE, Choo JR, Goh BC, et al. Third generation EGFR TKIs: current data and future directions. Mol Cancer. 2018;17:29.
Zalaquett Z, Catherine Rita Hachem M, Kassis Y, Hachem S, Eid R, Raphael Kourie H, et al. Acquired resistance mechanisms to osimertinib: the constant battle. Cancer Treat Rev. 2023;116:102557.
Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.
Cooper AJ, Sequist LV, Lin JJ. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol. 2022;19:499–514.
He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6:425.
Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388:2058–70.
Mullard A. FDA approves first-in-class AKT inhibitor. Nat Rev Drug Discov. 2024;23:9.
Worby CA, Dixon JE. PTEN. Annu Rev Biochem. 2014;83:641–69.
McLoughlin NM, Mueller C, Grossmann TN. The therapeutic potential of PTEN modulation: targeting strategies from gene to protein. Cell Chem Biol. 2018;25:19–29.
Boosani CS, Gunasekar P, Agrawal DK. An update on PTEN modulators–a patent review. Expert Opin Ther Pat. 2019;29:881–9.
Ding L, Zhang Z, Liang G, Yao Z, Wu H, Wang B, et al. SAHA triggered MET activation contributes to SAHA tolerance in solid cancer cells. Cancer Lett. 2015;356:828–36.
Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55.
Chou TC, Talalay P. Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem. 1981;115:207–16.
Qian M, Yan F, Wang W, Du J, Yuan T, Wu R, et al. Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression. Acta Pharm Sin B. 2021;11:4008–19.
Shi P, Oh YT, Zhang G, Yao W, Yue P, Li Y, et al. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett. 2016;380:494–504.
Wang Y, Tian P, Xia L, Li L, Han R, Zhu M, et al. The clinical efficacy of combinatorial therapy of EGFR-TKI and crizotinib in overcoming MET amplification-mediated resistance from prior EGFR-TKI therapy. Lung Cancer. 2020;146:165–73.
Zeng L, Yang N, Zhang Y. GOPC-ROS1 rearrangement as an acquired resistance mechanism to osimertinib and responding to crizotinib combined treatments in lung adenocarcinoma. J Thorac Oncol. 2018;13:e114–6.
Li H, Tong CW, Leung Y, Wong MH, To KK, Leung KS. Identification of clinically approved drugs indacaterol and canagliflozin for repurposing to treat epidermal growth factor tyrosine kinase inhibitor-resistant lung cancer. Front Oncol. 2017;7:288.
Csanády L, Vergani P, Gadsby DC. Structure, gating, and regulation of the cftr anion channel. Physiol Rev. 2019;99:707–38.
Hanssens LS, Duchateau J, Casimir GJ. CFTR protein: not just a chloride channel? cells. 2021;10:2844.
Mall MA, Hartl D. CFTR: cystic fibrosis and beyond. Eur Respir J. 2014;44:1042–54.
Riquelme SA, Hopkins BD, Wolfe AL, DiMango E, Kitur K, Parsons R, et al. Cystic fibrosis transmembrane conductance regulator attaches tumor suppressor PTEN to the membrane and promotes anti pseudomonas aeruginosa immunity. Immunity. 2017;47:1169–81.e1167.
Manders EM, Verbeek F, Aten J. Measurement of co‐localization of objects in dual‐colour confocal images. J Microsc. 1993;169:375–82. JJom
Adler J, Parmryd I. Quantifying colocalization by correlation: the Pearson correlation coefficient is superior to the Mander’s overlap coefficient. Cytom A. 2010;77:733–42.
Nguyen HN, Afkari Y, Senoo H, Sesaki H, Devreotes PN, Iijima M. Mechanism of human PTEN localization revealed by heterologous expression in Dictyostelium. Oncogene. 2014;33:5688–96.
Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19:547–62.
Deeks ED. Lumacaftor/ivacaftor: a review in cystic fibrosis. Drugs. 2016;76:1191–201.
Kashima K, Kawauchi H, Tanimura H, Tachibana Y, Chiba T, Torizawa T, et al. CH7233163 overcomes osimertinib-resistant EGFR-Del19/T790M/C797S mutation. Mol Cancer Ther. 2020;19:2288–97.
Eno MS, Brubaker JD, Campbell JE, De Savi C, Guzi TJ, Williams BD, et al. Discovery of BLU-945, a reversible, potent, and wild-type-sparing next-generation EGFR mutant inhibitor for treatment-resistant non-small-cell lung cancer. J Med Chem. 2022;65:9662–77.
Lim SM, Fujino T, Kim C, Lee G, Lee YH, Kim DW, et al. BBT-176, a novel fourth-generation tyrosine kinase inhibitor for osimertinib-resistant EGFR mutations in non-small cell lung cancer. Clin Cancer Res. 2023;29:3004–16.
Fu K, Xie F, Wang F, Fu L. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J Hematol Oncol. 2022;15:173.
Parisi GF, Papale M, Pecora G, Rotolo N, Manti S, Russo G, et al. Cystic fibrosis and cancer: unraveling the complex role of CFTR gene in cancer susceptibility. Cancers. 2023;15:4244.
Than BL, Linnekamp JF, Starr TK, Largaespada DA, Rod A, Zhang Y, et al. CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene. 2016;35:4179–87.
Zhang JT, Jiang XH, Xie C, Cheng H, Da Dong J, Wang Y, et al. Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. Biochim Biophys Acta. 2013;1833:2961–9.
Son JW, Kim YJ, Cho HM, Lee SY, Lee SM, Kang JK, et al. Promoter hypermethylation of the CFTR gene and clinical/pathological features associated with non-small cell lung cancer. Respirology. 2011;16:1203–9.
Li J, Zhang JT, Jiang X, Shi X, Shen J, Feng F, et al. The cystic fibrosis transmembrane conductance regulator as a biomarker in non-small cell lung cancer. Int J Oncol. 2015;46:2107–15.
Xiao Q, Koutsilieri S, Sismanoglou DC, Lauschke VM. CFTR reduces the proliferation of lung adenocarcinoma and is a strong predictor of survival in both smokers and non-smokers. J Cancer Res Clin Oncol. 2022;148:3293–302.
Liu K, Pu J, Nie Z, Shi Y, Jiang L, Wu Q, et al. Ivacaftor inhibits glioblastoma stem cell maintenance and tumor progression. Front Cell Dev Biol. 2021;9:678209.
Tanaka K, Yu HA, Yang S, Han S, Selcuklu SD, Kim K, et al. Targeting aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer Cell. 2021;39:1245–61.e1246.
Breuer W, Slotki IN, Ausiello DA, Cabantchik IZ. Induction of multidrug resistance downregulates the expression of CFTR in colon epithelial cells. Am J Physiol. 1993;265:C1711–5.
Kunzelmann K, Slotki IN, Klein P, Koslowsky T, Ausiello DA, Greger R, et al. Effects of P-glycoprotein expression on cyclic AMP and volume-activated ion fluxes and conductances in HT-29 colon adenocarcinoma cells. J Cell Physiol. 1994;161:393–406.
Skinner KT, Palkar AM, Hong AL. Genetics of ABCB1 in cancer. Cancers. 2023;15:4236.
Kurimchak AM, Herrera-Montávez C, Montserrat-Sangrà S, Araiza-Olivera D, Hu J, Neumann-Domer R, et al. The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells. Sci Signal. 2022;15:eabn2707.
Huang J, Pan B, Xia G, Zhu J, Li C, Feng J. LncRNA SNHG15 regulates EGFR-TKI acquired resistance in lung adenocarcinoma through sponging miR-451 to upregulate MDR-1. Cell Death Dis. 2020;11:525.
Trezise AE, Romano PR, Gill DR, Hyde SC, Sepúlveda FV, Buchwald M, et al. The multidrug resistance and cystic fibrosis genes have complementary patterns of epithelial expression. EMBO J. 1992;11:4291–303.
Riquelme SA, Lozano C, Moustafa AM, Liimatta K, Tomlinson KL, Britto C, et al. CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection. Sci Transl Med. 2019;11:eaav4634.
Acknowledgements
This work was supported by Zhejiang Major R&D programs (2021C03042), Key R&D Program of Zhejiang Respiratory Disease (2023C03069), and Zhejiang Provincial Clinical Research Center for Respiratory Disease (2022E50005).
Author information
Authors and Affiliations
Contributions
YKL: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Data curation, Writing—original draft, Writing— review & editing. FJG: Conceptualization, Methodology, Investigation, Validation, Formal analysis, Data curation. XNL: Investigation, Formal analysis, Data curation. CMZ: Conceptualization, Methodology. MJQ: Methodology, Investigation. YHL: Investigation. MMZ: Resources. JJQ: Resources. LJF: Resources. JJL: Resources. BY: Resources, Supervision. QJH: Resources, Supervision. JYZ: Resources, Writing—review & editing, Supervision, Funding acquisition. HZ: Conceptualization, Methodology, Resources, Writing—review & editing, Supervision, Project administration, Funding acquisition. All the authors have read and approved the article.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Li, Yk., Ge, Fj., Liu, Xn. et al. Ivacaftor, a CFTR potentiator, synergizes with osimertinib against acquired resistance to osimertinib in NSCLC by regulating CFTR-PTEN-AKT axis. Acta Pharmacol Sin 46, 1045–1057 (2025). https://doi.org/10.1038/s41401-024-01427-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-024-01427-0
