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dc.contributor.authorVyse, Sen_US
dc.contributor.authorMcCarthy, Fen_US
dc.contributor.authorBroncel, Men_US
dc.contributor.authorPaul, Aen_US
dc.contributor.authorWong, JPen_US
dc.contributor.authorBhamra, Aen_US
dc.contributor.authorHuang, PHen_US
dc.date.accessioned2017-08-29T11:03:49Z
dc.date.issued2018-01en_US
dc.identifier.citationJournal of proteomics, 2018, 170 pp. 130 - 140en_US
dc.identifier.issn1874-3919en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/795
dc.identifier.eissn1876-7737en_US
dc.identifier.doi10.1016/j.jprot.2017.08.015en_US
dc.description.abstractAcquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.<h4>Significance</h4>Pazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy.en_US
dc.formatPrint-Electronicen_US
dc.format.extent130 - 140en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Line, Tumoren_US
dc.subjectHumansen_US
dc.subjectNeoplasmsen_US
dc.subjectSulfonamidesen_US
dc.subjectPyrimidinesen_US
dc.subjectNeoplasm Proteinsen_US
dc.subjectPhosphoproteinsen_US
dc.subjectSignal Transductionen_US
dc.subjectDrug Resistance, Neoplasmen_US
dc.subjectDasatiniben_US
dc.titleQuantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-08-17en_US
rioxxterms.versionofrecord10.1016/j.jprot.2017.08.015en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJournal of proteomicsen_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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Protein Networks
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular and Systems Oncology
pubs.publication-statusPublisheden_US
pubs.volume170en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamProtein Networksen_US
icr.researchteamMolecular and Systems Oncologyen_US
dc.contributor.icrauthorHuang, Paulen_US
dc.contributor.icrauthorVyse, Simonen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/