Data from Coactivated Platelet-Derived Growth Factor Receptor α and Epidermal Growth Factor Receptor Are Potential Therapeutic Targets in Intimal Sarcoma

作者：Barbara Dewaele, Giuseppe Floris, Julio Finalet-Ferreiro, Christopher D.�M. Fletcher, Jean‐Michel Coindre, Louis Guillou, Pancras C.W. Hogendoorn, Agnieszka Woźniak, Vanessa Vanspauwen, Patrick Schöffski, Peter Marynen, Peter Vandenberghe, Raf Sciot, Maria Dêbiec‐Rychter · 年份：2023 · DOI：10.1158/0008-5472.c.6500213.v1 · 研究领域：Sarcoma Diagnosis and Treatment、Cardiac tumors and thrombi、Lymphoma Diagnosis and Treatment

<div>AbstractIntimal 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 investigati...