Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes.
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Date
2017-08-15ICR Author
Author
Fleuren, EDG
Vlenterie, M
van der Graaf, WTA
Hillebrandt-Roeffen, MHS
Blackburn, J
Ma, X
Chan, H
Magias, MC
van Erp, A
van Houdt, L
Cebeci, SAS
van de Ven, A
Flucke, UE
Heyer, EE
Thomas, DM
Lord, CJ
Marini, KD
Vaghjiani, V
Mercer, TR
Cain, JE
Wu, J
Versleijen-Jonkers, YMH
Daly, RJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Animals
Mice, Inbred BALB C
Humans
Mice
Sarcoma, Synovial
Sulfonamides
Sulfones
Pyrazoles
Pyridines
Pyrimidines
Receptor Protein-Tyrosine Kinases
Receptor, Platelet-Derived Growth Factor alpha
Protein Kinase Inhibitors
Cohort Studies
Xenograft Model Antitumor Assays
Proteomics
Signal Transduction
Phosphorylation
Female
Proto-Oncogene Proteins c-met
Molecular Targeted Therapy
Crizotinib
Anaplastic Lymphoma Kinase
Research team
Clinical and Translational Sarcoma
Gene Function
Language
eng
Date accepted
2017-06-06
License start date
2017-08
Citation
Cancer research, 2017, 77 (16), pp. 4279 - 4292
Publisher
AMER ASSOC CANCER RESEARCH