Molecule Information

General Information of the Molecule (ID: Mol04335)

• Name: Cystic fibrosis transmembrane conductance regulator (CFTR) ,Homo sapiens
• Synonyms: ATP-binding cassette sub-family C member 7; Channel conductance-controlling ATPase; cAMP-dependent chloride channel
• Molecule Type: Protein
• Gene Name: CFTR
• Gene ID: 1080
• Sequence:
  MQRSPLEKASVVSKLFFSWTRPILRKGYRQRLELSDIYQIPSVDSADNLSEKLEREWDRE
  LASKKNPKLINALRRCFFWRFMFYGIFLYLGEVTKAVQPLLLGRIIASYDPDNKEERSI
  A IYLGIGLCLLFIVRTLLLHPAIFGLHHIGMQMRIAMFSLIYKKTLKLSSRVLDKISIG
  QL VSLLSNNLNKFDEGLALAHFVWIAPLQVALLMGLIWELLQASAFCGLGFLIVLALFQ
  AGL GRMMMKYRDQRAGKISERLVITSEMIENIQSVKAYCWEEAMEKMIENLRQTELKLT
  RKAA YVRYFNSSAFFFSGFFVVFLSVLPYALIKGIILRKIFTTISFCIVLRMAVTRQFP
  WAVQT WYDSLGAINKIQDFLQKQEYKTLEYNLTTTEVVMENVTAFWEEGFGELFEKAKQ
  NNNNRK TSNGDDSLFFSNFSLLGTPVLKDINFKIERGQLLAVAGSTGAGKTSLLMVIMG
  ELEPSEG KIKHSGRISFCSQFSWIMPGTIKENIIFGVSYDEYRYRSVIKACQLEEDISK
  FAEKDNIV LGEGGITLSGGQRARISLARAVYKDADLYLLDSPFGYLDVLTEKEIFESCV
  CKLMANKTR ILVTSKMEHLKKADKILILHEGSSYFYGTFSELQNLQPDFSSKLMGCDSF
  DQFSAERRNS ILTETLHRFSLEGDAPVSWTETKKQSFKQTGEFGEKRKNSILNPINSIR
  KFSIVQKTPLQ MNGIEEDSDEPLERRLSLVPDSEQGEAILPRISVISTGPTLQARRRQS
  VLNLMTHSVNQG QNIHRKTTASTRKVSLAPQANLTELDIYSRRLSQETGLEISEEINEE
  DLKECFFDDMESI PAVTTWNTYLRYITVHKSLIFVLIWCLVIFLAEVAASLVVLWLLGN
  TPLQDKGNSTHSRN NSYAVIITSTSSYYVFYIYVGVADTLLAMGFFRGLPLVHTLITVS
  KILHHKMLHSVLQAP MSTLNTLKAGGILNRFSKDIAILDDLLPLTIFDFIQLLLIVIGA
  IAVVAVLQPYIFVATV PVIVAFIMLRAYFLQTSQQLKQLESEGRSPIFTHLVTSLKGLW
  TLRAFGRQPYFETLFHK ALNLHTANWFLYLSTLRWFQMRIEMIFVIFFIAVTFISILTT
  GEGEGRVGIILTLAMNIM STLQWAVNSSIDVDSLMRSVSRVFKFIDMPTEGKPTKSTKP
  YKNGQLSKVMIIENSHVKK DDIWPSGGQMTVKDLTAKYTEGGNAILENISFSISPGQRV
  GLLGRTGSGKSTLLSAFLRL LNTEGEIQIDGVSWDSITLQQWRKAFGVIPQKVFIFSGT
  FRKNLDPYEQWSDQEIWKVAD EVGLRSVIEQFPGKLDFVLVDGGCVLSHGHKQLMCLAR
  SVLSKAKILLLDEPSAHLDPVT YQIIRRTLKQAFADCTVILCEHRIEAMLECQQFLVIE
  ENKVRQYDSIQKLLNERSLFRQA ISPSDRVKLFPHRNSSKCKSKPQIAALKEETEEEVQ
  DTRL
• Function: Epithelial ion channel that plays an important role in theregulation of epithelial ion and water transport and fluid homeostasis. Mediates the transport of chloride ions across thecell membrane .Possesses an intrinsic ATPase activity and utilizes ATP to gate itschannel; the passive flow of anions through the channel is gated bycycles of ATP binding and hydrolysis by the ATP-binding domains.The ion channel is also permeable to HCO; selectivity depends onthe extracellular chloride concentration . In vitro, mediates ATP-dependent glutathione flux. Exerts its function also by modulating the activityof other ion channels and transporters . Plays an importantrole in airway fluid homeostasis . Contributes to the regulation of the pH and the ioncontent of the airway surface fluid layer and thereby plays animportant role in defense against pathogens . Modulates the activity of theepithelial sodium channel complex, in part by regulating thecell surface expression of the ENaC complex . Inhibits the activity of the ENaCchannel containing subunits SCNN1A, SCNN1B and SCNN1G. Inhibits the activity of the ENaC channel containingsubunits SCNN1D, SCNN1B and SCNN1G, but not of the ENaC channelcontaining subunits SCNN1A, SCNN1B and SCNN1G . May regulate bicarbonate secretion and salvage inepithelial cells by regulating the transporter SLC4A7. Can inhibit the chloride channel activity of ANO1. Plays a role in the chloride and bicarbonatehomeostasis during sperm epididymal maturation and capacitation.{ECO:0000269|PubMed:10792060, ECO:0000269|PubMed:11524016,ECO:0000269|PubMed:11707463, ECO:0000269|PubMed:12403779,ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:12529365,ECO:0000269|PubMed:12588899, ECO:0000269|PubMed:12727866,ECO:0000269|PubMed:14668433, ECO:0000269|PubMed:15010471,ECO:0000269|PubMed:15284228, ECO:0000269|PubMed:16645176,ECO:0000269|PubMed:17036051, ECO:0000269|PubMed:1712898,ECO:0000269|PubMed:17182731, ECO:0000269|PubMed:19019741,ECO:0000269|PubMed:19398555, ECO:0000269|PubMed:19621064,ECO:0000269|PubMed:22178883, ECO:0000269|PubMed:25330774,ECO:0000269|PubMed:26627831, ECO:0000269|PubMed:26823428,ECO:0000269|PubMed:26846474, ECO:0000269|PubMed:27714810,ECO:0000269|PubMed:27941075, ECO:0000269|PubMed:28087700,ECO:0000269|PubMed:29393851, ECO:0000269|PubMed:8910473,ECO:0000269|PubMed:9804160, ECO:0000305|PubMed:19923167}.
• Uniprot ID: CFTR_HUMAN
• Ensembl ID: ENSG0000000162618
• HGNC ID: HGNC:1884

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Ivacaftor

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: Ivacaftor
• 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.

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K+Akt signaling pathway; Activation; 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: 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.