# Fibroblast growth factor receptor alterations and resistance mechanisms in the treatment of pediatric solid tumors

## TL;DR

This paper explores FGFR gene changes in pediatric cancers and tests a drug that could help treat some of these tumors.

## Contribution

The study identifies FGFR overexpression in pediatric neuroblastoma and evaluates the effectiveness of FGFR inhibitors in preclinical models.

## Key findings

- FGFR gene alterations are rare in pediatric cancers compared to adult cancers.
- FGFR1-4 overexpression in neuroblastoma is linked to patient outcomes.
- The FGFR inhibitor BGJ398 reduces cancer cell proliferation and activates cell death pathways.

## Abstract

Aim: The fibroblast growth factor receptor (FGFR) family receptors regulate cell proliferation, survival, and migration and are linked to cancer drug resistance. FGFR gene family alterations have been found in multiple adult cancers, for which FGFR inhibitors are in various stages of clinical development. This study aimed to delineate the FGFR alterations in pediatric tumors and provide a preclinical rationale for developing FGFR inhibitors for select pediatric patients.

Methods: The prevalence of FGFR alterations in pediatric cancers was calculated from databases with available pediatric tumor data. Effects of the pan-FGFR inhibitor infigratinib (BGJ398) on pediatric cancer cell line viability and migration were evaluated by continuous live cell imaging and compared to FGFR gene expression. Effects on cell death and signaling pathway activity were evaluated by live cell imaging and Western blots.

Results: Overall rates of FGFR1-4 gene alterations in pediatric cancers were rare, and the mutation profile substantially differs from that of adult tumors. Although FGFR genomic alterations are rare in pediatric neuroblastoma tumors, overexpression of FGFR1-4 is observed in tumor subsets and is associated with outcomes. Dose-dependent inhibition of cell proliferation and migration and promotion of cell death were achieved with BGJ398 treatment in neuroblastoma cell lines, accompanied by inhibition of RAS-MAPK pathway activity and induction of apoptosis.

Conclusion: Adult and pediatric cancers share common mechanisms of FGFR activation but differ in overall alteration rates and relative abundance of specific aberrations. Preliminary experimental data indicate the therapeutic potential of FGFR inhibitors and suggest mechanisms of resistance in the treatment of pediatric cancers.