Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity

• Published in: Carcinogenesis (New York) Vol. 27; no. 3; pp. 664 - 671
• Main Authors: Holtkamp, Nikola, Okuducu, Ali Fuat, Mucha, Jana, Afanasieva, Anastasia, Hartmann, Christian, Atallah, Isis, Estevez-Schwarz, Lope, Mawrin, Christian, Friedrich, Reinhard E., Mautner, Victor-F., von Deimling, Andreas
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.03.2006; Oxford Publishing Limited (England)
• Subjects: Antineoplastic Agents - pharmacology; Benzamides; Biological and medical sciences; Cancer; Carcinogenesis, carcinogens and anticarcinogens; dimethylsulfoxide; DMSO; Exons; gastrointestinal stromal tumours; Gene Amplification; Gene Expression Profiling; GIST; Humans; Imatinib Mesylate; malignant peripheral nerve sheath tumours; Medical sciences; MPNST; Nerve Sheath Neoplasms - drug therapy; Nerve Sheath Neoplasms - genetics; Nerve Sheath Neoplasms - physiopathology; neurofibromatosis type 1; Neurology; NF1; PDGFRα; Piperazines - pharmacology; platelet-derived growth factor receptor alpha; plexiform neurofibromas; pNF; Polymorphism, Genetic; Proto-Oncogene Proteins c-kit - biosynthesis; Proto-Oncogene Proteins c-kit - genetics; Pyrimidines - pharmacology; Receptor, Platelet-Derived Growth Factor alpha - biosynthesis; Receptor, Platelet-Derived Growth Factor alpha - genetics; Tumor Cells, Cultured; Tumors; Tumors of the nervous system. Phacomatoses; Antineoplastic agent; Peripheral nerve; Platelet derived growth factor receptor A; Nervous system diseases; Imatinib; Enzyme; Transferases; Neurinoma; Enzyme inhibitor; Malignant tumor; Sensitivity; Kit; Genetics; Benign neoplasm; Mutation; kit Gene; Protein-tyrosine kinase
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi273

Platelet-derived growth factor receptor alpha (PDGFRα) and c-Kit are receptor tyrosine kinases. Both are targets of the tyrosine kinase inhibitor imatinib mesylate which is approved for treatment of some cancers. In order to assess the role of PDGFRα and c-Kit in malignant peripheral nerve sheath tumours (MPNST) we examined human tumours for structural alterations, protein and ligand expression. We investigated 34 MPNST, 6 corresponding plexiform neurofibromas (pNF) and 1 MPNST cell culture from 31 patients for mutations and polymorphisms in PDGFRA (exon 2–21) and KIT (exon 9, 11, 13, 17). PDGFRA was amplified in seven tumours from six patients and MPNST cell culture S462. KIT was amplified in five tumours from four patients and in the cell culture. Two MPNST carried somatic PDGFRA mutations in exons coding for the extracellular domain. In addition we detected several polymorphisms in PDGFRA. No point mutations or polymorphisms were detected in the four KIT exons analysed. PDGFRα expression was present in 21 of 28 MPNST patients (75%) and the MPNST cell culture. Expression analysis of PDGFRα ligands in MPNST and neurofibromas revealed that PDGF-A was more widely expressed than PDGF-B. Focal c-Kit expression was detected in 2 of 29 (7%) MPNST patients. Imatinib treatment of MPNST cell culture S462 exerted a growth inhibitory effect and prevented PDGF-AA induced PDGFRα phosphorylation. In summary, PDGFRA, PDGF and KIT dysregulation as well as growth inhibition of cell culture S462 by imatinib may suggest that MPNST patients benefit from treatment with imatinib.