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

Abstract

Platelet-derived growth factor receptor alpha (PDGFRalpha) 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 PDGFRalpha 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. PDGFRalpha expression was present in 21 of 28 MPNST patients (75%) and the MPNST cell culture. Expression analysis of PDGFRalpha 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 PDGFRalpha 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.

• Authors: Nikola Holtkamp, Ali Fuat Okuducu, Jana Mucha, Anastasia Afanasieva, Christian Hartmann, Isis Atallah, Lope Estevez-Schwarz, Christian Mawrin, Reinhard E Friedrich, Victor-F Mautner, Andreas von Deimling
• Journal: Carcinogenesis (Carcinogenesis) Vol. 27 Issue 3 Pg. 664-71 (Mar 2006) ISSN: 0143-3334 [Print] England
• PMID: 16357008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Proto-Oncogene Proteins c-kit
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Antineoplastic Agents (pharmacology)
• Benzamides
• Exons
• Gene Amplification
• Gene Expression Profiling
• Humans
• Imatinib Mesylate
• Nerve Sheath Neoplasms (drug therapy, genetics, physiopathology)
• Piperazines (pharmacology)
• Polymorphism, Genetic
• Proto-Oncogene Proteins c-kit (biosynthesis, genetics)
• Pyrimidines (pharmacology)
• Receptor, Platelet-Derived Growth Factor alpha (biosynthesis, genetics)
• Tumor Cells, Cultured