dc.contributor.author | Fleuren, EDG | |
dc.contributor.author | Vlenterie, M | |
dc.contributor.author | van der Graaf, WTA | |
dc.contributor.author | Hillebrandt-Roeffen, MHS | |
dc.contributor.author | Blackburn, J | |
dc.contributor.author | Ma, X | |
dc.contributor.author | Chan, H | |
dc.contributor.author | Magias, MC | |
dc.contributor.author | van Erp, A | |
dc.contributor.author | van Houdt, L | |
dc.contributor.author | Cebeci, SAS | |
dc.contributor.author | van de Ven, A | |
dc.contributor.author | Flucke, UE | |
dc.contributor.author | Heyer, EE | |
dc.contributor.author | Thomas, DM | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Marini, KD | |
dc.contributor.author | Vaghjiani, V | |
dc.contributor.author | Mercer, TR | |
dc.contributor.author | Cain, JE | |
dc.contributor.author | Wu, J | |
dc.contributor.author | Versleijen-Jonkers, YMH | |
dc.contributor.author | Daly, RJ | |
dc.date.accessioned | 2017-07-05T11:06:09Z | |
dc.date.issued | 2017-08-15 | |
dc.identifier.citation | Cancer research, 2017, 77 (16), pp. 4279 - 4292 | |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/682 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.doi | 10.1158/0008-5472.can-16-2550 | |
dc.description.abstract | Despite 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 (ALKΔ2-17). 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.format | Print-Electronic | |
dc.format.extent | 4279 - 4292 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Sarcoma, Synovial | |
dc.subject | Sulfonamides | |
dc.subject | Sulfones | |
dc.subject | Pyrazoles | |
dc.subject | Pyridines | |
dc.subject | Pyrimidines | |
dc.subject | Receptor Protein-Tyrosine Kinases | |
dc.subject | Receptor, Platelet-Derived Growth Factor alpha | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Cohort Studies | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Proteomics | |
dc.subject | Signal Transduction | |
dc.subject | Phosphorylation | |
dc.subject | Female | |
dc.subject | Proto-Oncogene Proteins c-met | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Crizotinib | |
dc.subject | Anaplastic Lymphoma Kinase | |
dc.title | Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-06-06 | |
rioxxterms.versionofrecord | 10.1158/0008-5472.can-16-2550 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2017-08 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer research | |
pubs.issue | 16 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 77 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical and Translational Sarcoma | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Lord, Christopher | |