Abstract
Abstract BACKGROUND Low-grade gliomas (LGGs) are the most common central nervous system (CNS) tumor found in children, comprising nearly one-third of all diagnoses. Fifteen to twenty percent of pediatric LGGs arise due to mutations in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, most commonly at the B-Raf proto-oncogene (BRAF) gene. Modern advances in personalized medicine have led to widespread use of targeted therapies to treat pediatric LGGs, specifically pan-RAF inhibitors that target BRAF V600E missense mutations and KIAA1549:BRAF fusions. However, to date, very few RAF inhibitors have been approved for use in children. METHODS The present study utilized patient-derived pediatric LGG cell lines to investigate the efficacy of Belvarafenib (0.5nM to 5nM), a type II pan-RAF inhibitor, as a potential therapeutic agent to treat BRAF-altered pediatric LGGs. A recent study demonstrated Belvarafenib’s ability to cross the blood-brain barrier, leading to an interest in its potential use in BRAF-mutated pediatric brain tumors. Belvarafenib has already shown promise in treating BRAF V600E-mutated melanomas and other solid tumors in adults, although its ability to effectively target BRAF fusions is unclear. Hence, three pediatric patient-derived cell lines with BRAF fusions will help elucidate any effect from Belvarafenib. RESULTS When treated with Belvarafenib, the cell lines harboring BRAF fusions demonstrated the compound’s inability to significantly decrease tumor cell viability. CONCLUSIONS This preliminary data highlights the possible limitations associated with using Belvarafenib as a single agent to treat pediatric LGGs with BRAF fusions.
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