title: Coactivated platelet-derived growth factor receptor {alpha} and epidermal growth factor receptor are potential therapeutic targets in intimal sarcoma.
abstract: Intimal sarcoma (IS) 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 IS were analyzed by immunohistochemistry and fluorescence in situ hybridization and selectively by karyotyping, array comparative genomic hybridization, 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 IS primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib. We showed that amplification of platelet-derived growth factor receptor α (PDGFRA) is a common finding in IS, 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 coexist with amplification and overexpression of the MDM2 oncogene. Ex vivo immunoassays on primary IS 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 IS. Given the clonal heterogeneity of this tumor type and the potential cross-talk between the PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve the therapeutic outcome for patients with this disease.
authors.affiliation: Department of Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dewaele
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.forename: Julio
authors.initials: J
authors.lastname: Finalet-Ferreiro
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Louis
authors.initials: L
authors.lastname: Guillou
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Vanessa
authors.initials: V
authors.lastname: Vanspauwen
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides; D055028:Comparative Genomic Hybridization; D000069439:Dasatinib; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology; D019043:Vascular Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000069439:Dasatinib