Coactivated Platelet-Derived Growth Factor Receptor α 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.

Single-Center Experience with Intimal Sarcoma, an Ultra-Orphan, Commonly Fatal Mesenchymal Malignancy

“…Bode-Lesniewska et al [18] showed in their series gains and amplifications of the 12q13-14 region and overexpression of MDM2. Amplification and upregulation of the MDM2 oncogene represents a molecular feature of many sarcomas, and is also reported in up to 70% of intimal sarcomas [1,9,[18][19][20]. In our institution, Dewaele et al [9] found that PDGFRA activation is commonly linked with activation of EGFR, and that this RTK coactivation may coexist with amplification and overexpression of MDM2 in these tumors.…”

“…Notably, these tumors show EGFR activation, concurrent to the PDGFRA activation. Moreover, this RTK co-activation may coexist with amplification and overexpression of MDM2 [8,9]. The differential diagnosis of initimal sarcoma includes angiosarcoma and leiomyosarcoma of the vessel wall.…”

Aortic Intimal Sarcoma Contributes to Atherosclerotic Renovascular Hypertension: An Autopsy Case Report and Review of the Literature

“…Radiation therapy with adjuvant doxorubicin and ifosfamide chemotherapy is associated with a response rate of up to 20% (14,16). Recently, Dewaele et al reported the potential of molecular target treatment against the genes coding for platelet-derived growth factor receptor-α (PDGFRA), epidermal growth factor receptor (EGFR), or MDM2 in AIS (17). The clinical course of the patient herein described presents two important issues.…”

Uncommon Case of Brain Metastasis in a Patient with a History of Heavy Smoking

“…In a high percentage of intimal sarcomas (70%-80%), overexpression of the Mdm2 protein can be observed 19,20 ; however, this finding is not specific, because many other tumours can also show this staining pattern.…”

“…Further, activated pdgfra and epidermal growth factor receptor frequently coexist with amplification and overexpression of the MDM2 oncogene. Therapies that target pdgfra, epidermal growth factor receptor, or Mdm2 in intimal sarcomas therefore seem to be a reasonable approach to this rare tumour entity 19 . …”