Biological and clinical implications of FGFR aberrations in paediatric and young adult cancers

Brown, LM; Ekert, PG; Fleuren, EDG

Author(s): Brown, LM; Ekert, PG; Fleuren, EDG;
Details: Publication Year 2023-06,Volume 42,Issue #23,Page 1875-1888
Journal Title: Oncogene
Publication Type: Review
Abstract: Rare but recurrent mutations in the fibroblast growth factor receptor (FGFR) pathways, most commonly in one of the four FGFR receptor tyrosine kinase genes, can potentially be targeted with broad-spectrum multi-kinase or FGFR selective inhibitors. The complete spectrum of these mutations in paediatric cancers is emerging as precision medicine programs perform comprehensive sequencing of individual tumours. Identification of patients most likely to benefit from FGFR inhibition currently rests on identifying activating FGFR mutations, gene fusions, or gene amplification events. However, the expanding use of transcriptome sequencing (RNAseq) has identified that many tumours overexpress FGFRs, in the absence of any genomic aberration. The challenge now presented is to determine when this indicates true FGFR oncogenic activity. Under-appreciated mechanisms of FGFR pathway activation, including alternate FGFR transcript expression and concomitant FGFR and FGF ligand expression, may mark those tumours where FGFR overexpression is indicative of a dependence on FGFR signalling. In this review, we provide a comprehensive and mechanistic overview of FGFR pathway aberrations and their functional consequences in paediatric cancer. We explore how FGFR over expression might be associated with true receptor activation. Further, we discuss the therapeutic implications of these aberrations in the paediatric setting and outline current and emerging therapeutic strategies to treat paediatric patients with FGFR-driven cancers.
Publisher: Springer Nature
Keywords: Humans; Young Adult; Child; *Receptors, Fibroblast Growth Factor; *Neoplasms/genetics/drug therapy; Signal Transduction/genetics; Mutation; Phosphorylation; Fibroblast Growth Factors/genetics/metabolism
Department(s): Laboratory Research
PubMed ID: 37130917
Publisher's Version: https://doi.org/10.1038/s41388-023-02705-7
Open Access at Publisher's Site: https://doi.org/10.1038/s41388-023-02705-7
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-08 01:31:23

Last Modified: 2023-08-08 01:31:53