Show simple item record

dc.contributor.authorFleuren, EDG
dc.contributor.authorVlenterie, M
dc.contributor.authorvan der Graaf, WTA
dc.contributor.authorHillebrandt-Roeffen, MHS
dc.contributor.authorBlackburn, J
dc.contributor.authorMa, X
dc.contributor.authorChan, H
dc.contributor.authorMagias, MC
dc.contributor.authorvan Erp, A
dc.contributor.authorvan Houdt, L
dc.contributor.authorCebeci, SAS
dc.contributor.authorvan de Ven, A
dc.contributor.authorFlucke, UE
dc.contributor.authorHeyer, EE
dc.contributor.authorThomas, DM
dc.contributor.authorLord, CJ
dc.contributor.authorMarini, KD
dc.contributor.authorVaghjiani, V
dc.contributor.authorMercer, TR
dc.contributor.authorCain, JE
dc.contributor.authorWu, J
dc.contributor.authorVersleijen-Jonkers, YMH
dc.contributor.authorDaly, RJ
dc.date.accessioned2017-07-05T11:06:09Z
dc.date.issued2017-08
dc.identifier.citationCancer research, 2017, 77 (16), pp. 4279 - 4292
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/682
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-16-2550
dc.description.abstractDespite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry-based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALK Δ2-17 ). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro , synergistic effects were observed upon drug combination. In vivo , both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res; 77(16); 4279-92. ©2017 AACR .
dc.formatPrint-Electronic
dc.format.extent4279 - 4292
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectMice, Inbred BALB C
dc.subjectHumans
dc.subjectMice
dc.subjectSarcoma, Synovial
dc.subjectSulfonamides
dc.subjectSulfones
dc.subjectPyrazoles
dc.subjectPyridines
dc.subjectPyrimidines
dc.subjectReceptor Protein-Tyrosine Kinases
dc.subjectReceptor, Platelet-Derived Growth Factor alpha
dc.subjectProtein Kinase Inhibitors
dc.subjectCohort Studies
dc.subjectXenograft Model Antitumor Assays
dc.subjectProteomics
dc.subjectSignal Transduction
dc.subjectPhosphorylation
dc.subjectFemale
dc.subjectProto-Oncogene Proteins c-met
dc.subjectMolecular Targeted Therapy
dc.subjectCrizotinib
dc.subjectAnaplastic Lymphoma Kinase
dc.titlePhosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes.
dc.typeJournal Article
dcterms.dateAccepted2017-06-06
rioxxterms.versionofrecord10.1158/0008-5472.can-16-2550
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer research
pubs.issue16
pubs.notesNot known
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/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical and Translational Sarcoma
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
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/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical and Translational Sarcoma
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume77
pubs.embargo.termsNot known
icr.researchteamClinical and Translational Sarcomaen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorvan der Graaf, Wilhelminaen
dc.contributor.icrauthorLord, Christopheren


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record