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Title: Co-activated PDGFRA and EGFR are potential therapeutic targets in intimal sarcoma
Authors: Dewaele, Barbara
Floris, Guiseppe
Finalet-Ferreiro, Julio
Fletcher, Christopher
Coindre, Jean Michel
Guillou, Louis
Hogendoorn, Pancras C
Wozniak, Agnieszka
Vanspauwen, Vanessa
Schöffski, Patrick
Marynen, Peter
Vandenberghe, Peter
Sciot, Raphael
Debiec-Rychter, Maria # ×
Issue Date: Aug-2010
Publisher: Waverly Press
Series Title: Cancer Research vol:70 issue:18 pages:7304-7314
Abstract: Intimal sarcoma is a rare, malignant and aggressive tumor that shows a relentless course with a concomitant low survival rate, and for which no effective treatment is available. In this study, 21 cases of large arterial blood vessel intimal sarcomas were analyzed by immunohistochemistry and fluorescent in situ hybridization, and selectively by karyotyping, array-CGH, sequencing, phospho-kinase antibody arrays and Western immunoblotting, in search for novel diagnostic markers and potential molecular therapeutic targets. Ex vivo immunoassays were applied to test the sensitivity of intimal sarcoma primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib. We demonstrated that amplification of the platelet-derived growth factor receptor alpha (PDGFRA) is a common finding in intimal sarcoma, which should be considered as a molecular hallmark of this entity. This amplification is consistently associated with PDGFRA activation. Furthermore, the tumors reveal persistent activation of the epidermal growth factor receptor (EGFR), concurrent to PDGFRA activation. Activated PDGFRA and EGFR frequently co-exist with amplification and overexpression of the MDM2 oncogene. Ex vivo immunoassays on primary intimal sarcoma cells from one case showed the potency of dasatinib to inhibit PDGFRA and downstream signaling pathways. Our findings provide a rationale for investigating therapies that target PDGFRA, EGFR or MDM2 in intimal sarcoma. Given the clonal heterogeneity of this tumor type and the potential crosstalk between PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve therapeutic outcome for patients with this disease.
URI: 
ISSN: 0008-5472
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Experimental Oncology
Translational Cell & Tissue Research
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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