Recurrent FGFR-alterations are frequent oncogenic drivers and therapeutic targets in pediatric low-grade gliomas [RNA-seq]
Alterations in Fibroblast growth factor receptor proteins frequently occur as oncogenes in many cancers. FGFR alterations have been reported in a subset of pediatric gliomas, representing a therapeutic target for precision medicine approaches. We performed a genomic analysis of 13,659 gliomas and found that 4.5% harbor FGFR alterations including structural variants and single nucleotide variants. FGFR family members are differentially enriched by age, tumor grade, and histological subtype. FGFR1 alterations are most frequent in pediatric gliomas, particularly pediatric low-grade gliomas, while FGFR3 drivers were associated with adult gliomas. In vitro and in vivo functional studies confirm FGFR1 alterations to be sufficient to activate MAPK and mTOR signaling, drive gliomagenesis and activate neuronal transcriptional programs. FGFR1-driven models showed sensitivity to MAPK pathway inhibitors, including panFGFR inhibitors that are FDA approved for use in other cancers. While early FGFR inhibition was sufficient to prolong survival of mice bearing FGFR-driven xenografts, this was insufficient to induce cures. Similarly, review of patients treated with currently available MAPK pathway or FGFR inhibitors revealed modest responses. This study provides key insights into the biology of FGFR1-altered gliomas and potential strategies to therapeutically target them. Overall design: To investigate the role of FGFR1 alterations in gliomagenesis in pLGGs, we engineered mouse neural stem cells (NSCs) to overexpress FGFR1 or BRAF alterations found in pLGGs. We then performed RNA-seq to look at their transcriptional programs on 8 different conditions (3 replicates).