Drug Information

Drug (ID: DG01238) and It's Reported Resistant Information

• Name: Ivacaftor
• Synonyms: Ivacaftor; 873054-44-5; VX-770; Kalydeco; Ivacaftor (VX-770); N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide; VX 770; VX770; UNII-1Y740ILL1Z; N-[2,4-Bis(tert-butyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide; CHEBI:66901; 1Y740ILL1Z; N-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide; 3-Quinolinecarboxamide, N-(2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl)-1,4-dihydro-4-oxo-; 1413431-05-6; 3-Quinolinecarboxamide, N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-; Kalydeco (TN); Ivacaftor [USAN:INN]; ivacaftorum; Ivacaftor D18; VX7; Ivacaftor (USAN/INN); VX-770 - Ivacaftor; MLS006011119; SCHEMBL351373; GTPL4342; VX-770, Ivacaftor, Kalydeco; CHEMBL2010601; DTXSID00236281; EX-A441; QCR-155; BCPP000199; HMS3654E10; HMS3744K05; AOB31714; BCP19794; BDBM50032693; MFCD17171361; s1144; ZINC52509463; AKOS015994762; AKOS032950001; BCP9000799; CCG-268562; CS-0497; DB08820; EX-7211; LE-0002; SB16815; N-(2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide; NCGC00242480-01; NCGC00242480-03; AC-28324; HY-13017; SMR004702900; FT-0696681; SW219620-1; X7565; EC-000.2478; A25626; D09916; AB01565806_02; Q6095693; CTP-656; CTP-656; CTP-656; d9-ivacaftor;VX-561; Cystic Fibrosis Transmembrane Conductance Regulator Potentiator; N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide; N-(2,4-ditert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide; N-(5-Hydroxy-2,4-bis(2-methyl-2-propanyl)phenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide; N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide; 1134822-00-6; Ivacaftor;N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide;Ivacaftor; Kalydeco; ; ; N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide
• Indication:
  In total 1 Indication(s)
  Cystic fibrosis [ICD-11: CA25]; Approved; [1]
• Target: cAMP-dependent chloride channel (CFTR); CFTR_HUMAN; [1]
• Formula: C24H28N2O3
• IsoSMILES: CC(C)(C)C1=CC(=C(C=C1NC(=O)C2=CNC3=CC=CC=C3C2=O)O)C(C)(C)C
• InChI: 1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)
• InChIKey: PURKAOJPTOLRMP-UHFFFAOYSA-N
• PubChem CID: 16220172
• ChEBI ID: CHEBI:66901
• TTD Drug ID: D0W7WC
• VARIDT ID: DR00466
• INTEDE ID: DR0898
• DrugBank ID: DB08820

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vivo Model: BALB/c female nude mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; Immunofluorescence staining assay; Immunohistochemistry; RNA sequencing assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay; EdU incorporation assay; Cell apoptosis assay
• Mechanism Description: 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.

Key Molecule: Cystic fibrosis transmembrane conductance regulator (CFTR) [2]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Function; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K-Akt signaling pathway; Inhibition; hsa04151
• In Vitro Model: PC-9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: HEK293 FT cells; Kidney; Homo sapiens (Human); CVCL_6911
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vivo Model: BALB/c female nude mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; Immunofluorescence staining assay; Immunohistochemistry; RNA sequencing assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay; EdU incorporation assay; Cell apoptosis assay
• Mechanism Description: 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.

References

• Ref 1: Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies .Nat Methods. 2020 Dec;17(12):1245-1253. doi: 10.1038/s41592-020-00992-6. Epub 2020 Nov 9. 10.1038/s41592-020-00992-6
• Ref 2: Ivacaftor, a CFTR potentiator, synergizes with osimertinib against acquired resistance to osimertinib in NSCLC by regulating CFTR-PTEN-AKT axis. Acta Pharmacol Sin. 2025 Apr;46(4):1045-1057.