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dc.contributor.authorWong, JP
dc.contributor.authorTodd, JR
dc.contributor.authorFinetti, MA
dc.contributor.authorMcCarthy, F
dc.contributor.authorBroncel, M
dc.contributor.authorVyse, S
dc.contributor.authorLuczynski, MT
dc.contributor.authorCrosier, S
dc.contributor.authorRyall, KA
dc.contributor.authorHolmes, K
dc.contributor.authorPayne, LS
dc.contributor.authorDaley, F
dc.contributor.authorWai, P
dc.contributor.authorJenks, A
dc.contributor.authorTanos, B
dc.contributor.authorTan, A-C
dc.contributor.authorNatrajan, RC
dc.contributor.authorWilliamson, D
dc.contributor.authorHuang, PH
dc.date.accessioned2016-11-23T12:40:22Z
dc.date.issued2016-10
dc.identifier.citationCell reports, 2016, 17 (5), pp. 1265 - 1275
dc.identifier.issn2211-1247
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/243
dc.identifier.eissn2211-1247en_US
dc.identifier.doi10.1016/j.celrep.2016.10.005en_US
dc.description.abstractSubunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies.
dc.formatPrint
dc.format.extent1265 - 1275
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectRhabdoid Tumor
dc.subjectSulfonamides
dc.subjectPyrimidines
dc.subjectPyrroles
dc.subjectIndoles
dc.subjectReceptor, Platelet-Derived Growth Factor alpha
dc.subjectGene Expression Profiling
dc.subjectApoptosis
dc.subjectDrug Resistance, Neoplasm
dc.subjectOncogenes
dc.subjectReceptor, Fibroblast Growth Factor, Type 1
dc.subjectDasatinib
dc.subjectSunitinib
dc.titleDual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors.
dc.typeJournal Article
dcterms.dateAccepted2016-09-30
rioxxterms.versionofrecord10.1016/j.celrep.2016.10.005
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-10en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCell reports
pubs.issue5
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
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/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular and Systems Oncology
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/Functional Genomics
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/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular and Systems Oncology
pubs.publication-statusPublished
pubs.volume17en_US
pubs.embargo.termsNo embargo
icr.researchteamProtein Networksen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamMolecular and Systems Oncologyen_US
dc.contributor.icrauthorTanos, Barbaraen
dc.contributor.icrauthorVyse, Simonen
dc.contributor.icrauthorLuczynski, Maciejen
dc.contributor.icrauthorHolmes, Katherineen
dc.contributor.icrauthorHuang, Paulen
dc.contributor.icrauthorNatrajan, Rachaelen


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