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dc.contributor.authorLi, H
dc.contributor.authorStokes, W
dc.contributor.authorChater, E
dc.contributor.authorRoy, R
dc.contributor.authorde Bruin, E
dc.contributor.authorHu, Y
dc.contributor.authorLiu, Z
dc.contributor.authorSmit, EF
dc.contributor.authorHeynen, GJ
dc.contributor.authorDownward, J
dc.contributor.authorSeckl, MJ
dc.contributor.authorWang, Y
dc.contributor.authorTang, H
dc.contributor.authorPardo, OE
dc.date.accessioned2017-11-08T12:41:56Z
dc.date.issued2016-01
dc.identifier.citationCell discovery, 2016, 2 pp. 16031 - ?
dc.identifier.issn2056-5968
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/905
dc.identifier.eissn2056-5968
dc.identifier.doi10.1038/celldisc.2016.31
dc.description.abstractEpidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.
dc.formatElectronic-eCollection
dc.format.extent16031 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleDecreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer.
dc.typeJournal Article
dcterms.dateAccepted2016-07-14
rioxxterms.versionofrecord10.1038/celldisc.2016.31
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCell discovery
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.publication-statusPublished
pubs.volume2
pubs.embargo.termsNo embargo
icr.researchteamLung Cancer Groupen_US
dc.contributor.icrauthorDownward, Julian David Harryen


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