FGFR alterations and potential role of FGFR inhibitors in pediatric brain tumors

Abstract A wide spectrum of genomic events leading to dysregulated fibroblast growth factor receptor (FGFR) signaling have been reported across low-grade and high-grade glial/glioneuronal tumors. These events include structural alterations, such as gene fusions and duplications, as well as recurrent mutations in FGFR1–3. Several FGFR-selective tyrosine kinase inhibitors (TKIs) have received regulatory approval for clinical use, and newer isoform-specific FGFR inhibitors are under investigation. Among pediatric patients with FGFR-altered low-grade gliomas (LGGs) enrolled on clinical trials with FGFR inhibitors, promising clinical efficacy regardless of alteration type (fusion or mutation) has been observed in a subset. In contrast, limited responses have been reported in adults with FGFR3–TACC3 fused IDH wild-type glioblastoma. FGFR inhibitor toxicities include hyperphosphatemia, diarrhea, skin, nail and ocular toxicity. Importantly, in skeletally immature patients, bone toxicities, such as accelerated growth spurts, limb fractures, and scoliosis, have been reported and require close monitoring. Co-occurring genomic alterations in MAPK pathway signaling components downstream of FGFR may drive intrinsic and acquired resistance to FGFR inhibitors. Further preclinical studies in relevant models of FGFR-altered pediatric gliomas are needed to help inform the development of novel, more effective and less toxic treatment strategies, as well as the rational design of clinical trials.