Effects of Sunitinib and Other Kinase Inhibitors on Cells Harboring a PDGFRB Mutation Associated with Infantile Myofibromatosis.

Abstract

Infantile myofibromatosis represents one of the most common proliferative fibrous tumors of infancy and childhood. More effective treatment is needed for drug-resistant patients, and targeted therapy using specific protein kinase inhibitors could be a promising strategy. To date, several studies have confirmed a connection between the p.R561C mutation in gene encoding platelet-derived growth factor receptor beta (PDGFR-beta) and the development of infantile myofibromatosis. This study aimed to analyze the phosphorylation of important kinases in the NSTS-47 cell line derived from a tumor of a boy with infantile myofibromatosis who harbored the p.R561C mutation in PDGFR-beta. The second aim of this study was to investigate the effects of selected protein kinase inhibitors on cell signaling and the proliferative activity of NSTS-47 cells. We confirmed that this tumor cell line showed very high phosphorylation levels of PDGFR-beta, extracellular signal-regulated kinases (ERK) 1/2 and several other protein kinases. We also observed that PDGFR-beta phosphorylation in tumor cells is reduced by the receptor tyrosine kinase inhibitor sunitinib. In contrast, MAPK/ERK kinases (MEK) 1/2 and ERK1/2 kinases remained constitutively phosphorylated after treatment with sunitinib and other relevant protein kinase inhibitors. Our study showed that sunitinib is a very promising agent that affects the proliferation of tumor cells with a p.R561C mutation in PDGFR-beta.

• Authors: Martin Sramek, Jakub Neradil, Petra Macigova, Peter Mudry, Kristyna Polaskova, Ondrej Slaby, Hana Noskova, Jaroslav Sterba, Renata Veselska
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 19 Issue 9 (Sep 01 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30200486 (Publication Type: Journal Article)

Chemical References

• Butadienes
• FR 180204
• Nitriles
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridazines
• U 0126
• Erlotinib Hydrochloride
• PDGFRB protein, human
• Receptor, Platelet-Derived Growth Factor beta
• Sunitinib

Topics

• Butadienes (administration & dosage, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Child
• Erlotinib Hydrochloride (administration & dosage, therapeutic use)
• Female
• Humans
• Infant
• Male
• Mutation
• Myofibromatosis (congenital, drug therapy, genetics)
• Nitriles (administration & dosage, therapeutic use)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (administration & dosage, therapeutic use)
• Pyrazoles (administration & dosage, therapeutic use)
• Pyridazines (administration & dosage, therapeutic use)
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)
• Sunitinib (administration & dosage, therapeutic use)