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dc.contributor.authorSava, GPen_US
dc.contributor.authorFan, Hen_US
dc.contributor.authorFisher, RAen_US
dc.contributor.authorLusvarghi, Sen_US
dc.contributor.authorPancholi, Sen_US
dc.contributor.authorAmbudkar, SVen_US
dc.contributor.authorMartin, L-Aen_US
dc.contributor.authorCharles Coombes, Ren_US
dc.contributor.authorBuluwela, Len_US
dc.contributor.authorAli, Sen_US
dc.date.accessioned2019-11-01T10:25:40Z
dc.date.issued2020-01en_US
dc.identifier.citationOncogene, 2020, 39 (3), pp. 651 - 663en_US
dc.identifier.issn0950-9232en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3398
dc.identifier.eissn1476-5594en_US
dc.identifier.doi10.1038/s41388-019-1008-yen_US
dc.description.abstractThe CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.en_US
dc.formatPrint-Electronicen_US
dc.format.extent651 - 663en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-08-24en_US
rioxxterms.versionofrecord10.1038/s41388-019-1008-yen_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2020-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfOncogeneen_US
pubs.issue3en_US
pubs.notesNo embargoen_US
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.publication-statusPublisheden_US
pubs.volume39en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamEndocrinologyen_US
dc.contributor.icrauthorPancholi, Sunilen_US


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