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.

• MeSH
• butadieny aplikace a dávkování   terapeutické užití   MeSH
• dítě MeSH
• erlotinib aplikace a dávkování   terapeutické užití   MeSH
• fosforylace účinky léků   MeSH
• inhibitory proteinkinas aplikace a dávkování   terapeutické užití   MeSH
• kojenec MeSH
• lidé MeSH
• mutace * MeSH
• myofibromatóza vrozené   farmakoterapie   genetika   MeSH
• nádorové buněčné linie MeSH
• nitrily aplikace a dávkování   terapeutické užití   MeSH
• proliferace buněk účinky léků   MeSH
• pyrazoly aplikace a dávkování   terapeutické užití   MeSH
• pyridaziny aplikace a dávkování   terapeutické užití   MeSH
• růstový faktor odvozený z trombocytů - receptor beta * genetika   metabolismus   MeSH
• sunitinib aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We aim to report the effect of oral ruxolitinib, the Janus kinase (JAK) family tyrosine kinase inhibitor, on clinical and immune status of a 12-year-old boy with severe CMC due to a novel STAT1 GOF mutation. METHODS: Clinical features and laboratory data were analyzed, particularly lymphocyte subsets, ex vivo IFNγ- and IFNα-induced STAT1, 3, 5 phosphorylation dynamics during the course of JAK1/2 inhibition therapy, and Th17-related, STAT1- and STAT3-inducible gene expression before and during the treatment. Sanger sequencing was used to detect the STAT1 mutation. Literature review of ruxolitinib in treatment of CMC is appended. RESULTS: A novel STAT1 GOF mutation (c.617T > C; p.L206P), detected in a child with recalcitrant CMC, was shown to be reversible in vitro with ruxolitinib. Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo. Clinical relapse and spike of all monitored phosphorylated STAT activity was registered shortly after unplanned withdrawal, decreasing again after ruxolitinib reintroduction. No increase of peripheral CD4+ IL17+ T cells was detected after 4 months of therapy. No adverse effects were noted. CONCLUSION: JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation.

• MeSH
• aktivační mutace * MeSH
• biologické markery MeSH
• CD4-pozitivní T-lymfocyty imunologie   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• dítě MeSH
• fosforylace MeSH
• genetická predispozice k nemoci MeSH
• imunofenotypizace MeSH
• inhibitory proteinkinas aplikace a dávkování   terapeutické užití   MeSH
• Janus kinasy antagonisté a inhibitory   MeSH
• kandidóza chronická mukokutánní diagnóza   farmakoterapie   genetika   metabolismus   MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• pyrazoly aplikace a dávkování   terapeutické užití   MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• transkripční faktor STAT1 genetika   metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH