A diverse landscape of FGFR alterations and co-mutations suggests potential therapeutic strategies in pediatric low-grade gliomas Journal Article
| Authors: | Apfelbaum, A. A.; Morin, E.; Sturm, D.; Ayoub, G.; DiGiacomo, J.; Bahadur, S.; Chandarana, B.; Power, P. C.; Cusick, M. M.; Novikov, D.; Prabhakar, P.; Jones, R. E.; Vogelzan, J.; Boss, C. C.; Malinowski, S.; Woodward, L.M.; Jones, T. A.; Jeang, J.; Lamson, S. W.; Collins, J.; Cai, K. Y.; Jones, J. S.; Oh, S.; Jeon, H.; Wang, J.; Cameron, A.; Rechter, P.; De Leon, A.; Murugesan, K.; Montesion, M.; Albacker, L. A.; Ramkissoon, S. H.; van Tilburg, C. M.; Hardin, E. C.; Sievers, P.; Sahm , F.; Yeo, K. K.; Rosenberg, T.; Chi, S. N.; Wright1. K. D.; Hébert, S.; Peck, S.; Picca, A.; Larouche, V.; Renzi, S.; Buhrlage, S. J.; Bale, T. A.; Smith, A. A.; Touat, M.; Jabado, N.; Fischer, E. S.; Eck, M. J.; Baird, L.; Witt, O.; Kleinman, C. L.; Nguyen, Q. D.; Sheer, D.; Alexandrescu, S.; Jones, D. T. W.; Ligon, K. L.; Bandopadhayay, P. |
| Article Title: | A diverse landscape of FGFR alterations and co-mutations suggests potential therapeutic strategies in pediatric low-grade gliomas |
| Abstract: | Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome. © 2025 Elsevier B.V., All rights reserved. |
| Keywords: | signal transduction; epidermal growth factor; mitogen activated protein kinase; protein kinase b; adolescent; child; controlled study; preschool child; child, preschool; retrospective studies; unclassified drug; gene mutation; genetics; mutation; histopathology; nonhuman; brain tumor; glioma; brain neoplasms; cancer grading; treatment indication; mouse; metabolism; animal tissue; disease association; carboplatin; phosphatase; animal experiment; animal model; protein; cohort analysis; vincristine; in vivo study; in vitro study; pathology; cell line, tumor; inhibitor; retrospective study; fibroblast growth factor receptor 3; histology; carcinogenesis; transcription regulation; infant; neuroblastoma; glioblastoma; mammalian target of rapamycin; medulloblastoma; tumor cell line; newborn; clinical evaluation; mitogen activated protein kinase 1; mitogen activated protein kinase 3; genomics; genetic stability; cyclin dependent kinase inhibitor 2a; tumor; drug therapy; nerve cell; mtor signaling; transcriptome; multiple cancer; everolimus; b raf kinase; brain hemorrhage; protein tyrosine phosphatase shp 2; fibroblast growth factor; receptor, fibroblast growth factor, type 1; fibroblast growth factor receptor 1; fibroblast growth factor receptor 2; pediatrics; fusion protein; landscape; meta analysis (topic); cyclin dependent kinase inhibitor 2b; gliomagenesis; protein s6; pilocytic astrocytoma; fibroblast growth factor receptor; tor serine-threonine kinases; target of rapamycin kinase; fibroblast growth factor receptor 4; mtor protein, human; trametinib; neoplasm grading; fgfr1 protein, human; humans; human; male; female; article; 4 aminobutyric acid receptor; nf1 protein; erdafitinib; infigratinib; pik3ca protein; pediatric patient; zoligratinib; debio 1347; nanodrop 2000; novaseq 6000; pik3r1 protein; low grade metamorphism |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-07-31 |
| Start Page: | 7018 |
| Language: | English |
| DOI: | 10.1038/s41467-025-61820-z |
| PUBMED: | 40744913 |
| PROVIDER: | scopus |
| PMCID: | PMC12314019 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
