Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for
Nikola Holtkamp1, Ali Fuat Okuducu, Jana Mucha
1Institute of Neuropathology, Charité - Universitätsmedizin Berlin, Germany. nikola.holtkamp@charite.de
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.
Insights
Platelet-derived growth factor receptor alpha (PDGFRalpha) and c-Kit are key in malignant peripheral nerve sheath tumors (MPNST). Imatinib inhibits MPNST cell growth, suggesting potential patient benefit from this targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers.
- Receptor tyrosine kinases, PDGFRalpha and c-Kit, are implicated in cancer growth.
- Imatinib mesylate targets these kinases and is used in cancer treatment.
Purpose of the Study:
- To investigate the role of PDGFRalpha and c-Kit in MPNST.
- To analyze genetic alterations and protein expression of PDGFRalpha and c-Kit in MPNST.
- To evaluate the effect of imatinib on MPNST cell growth.
Main Methods:
- Analysis of PDGFRA and KIT gene mutations and polymorphisms in 34 MPNST and 6 plexiform neurofibromas.
- Assessment of PDGFRalpha and c-Kit protein expression in tumor samples.
- In vitro study of imatinib's effect on MPNST cell culture S462.
Main Results:
- PDGFRA amplification occurred in 7 tumors and KIT amplification in 5 tumors.
- Two MPNSTs had somatic PDGFRA mutations; no KIT mutations were found.
- PDGFRalpha was expressed in 75% of MPNSTs; c-Kit was focally expressed in 7%.
- Imatinib inhibited MPNST cell culture growth and PDGFRalpha phosphorylation.
Conclusions:
- Dysregulation of PDGFRA, PDGF ligands, and KIT is observed in MPNST.
- Imatinib demonstrates growth inhibitory effects on MPNST cells.
- These findings suggest potential therapeutic benefit of imatinib for MPNST patients.
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