Application of a Translational Research Platform to Unveil Efficacy Signals and Mechanisms of Resistance of FGFR Inhibitors in Multiple FGFR -Altered Solid Tumors

PURPOSE: The predictive value of fibroblast growth factor receptor (FGFR) amplifications (amp) and the role of FGFR mutations (mut) beyond known activating variants remain unclear. We aimed to establish a translational research platform to characterize FGFR alterations (alt) and explore their potential as predictive biomarkers for FGFR-targeted agents. EXPERIMENTAL DESIGN: This ambispective study included a retrospective analysis of patients with FGFR-alt tumors treated with selective FGFR inhibitors (FGFRi) and a prospective collection of longitudinal tumor samples. Patient-derived xenografts (PDX) were generated to investigate FGFRi mechanisms of action and resistance. Molecular characterization included genomic, transcriptomic, proteomic, and functional analyses using the Functional Annotation for Cancer Treatment (FACT) assay. RESULTS: Among 36 retrospectively analyzed patients, clinical benefit from FGFRis was observed in cases with FGFR mRNA overexpression or FGFR2/11q co-amp, but no association was found with the amplification levels. In archival tumor samples, exploratory proteomic analysis showed FGFR1-4 protein expression in 78% of FGFR1/2-amp tumors detected by fluorescence in situ hybridization. RNA sequencing identified a higher prevalence of FGFR mRNA overexpression than proteomic analysis. Among patients harboring FGFR-mut, only one bladder cancer with an FGFR3-mut S249C derived benefit. FACT assay supported the functional activity of selected variants, including FGFR3 T689M, and suggested potential resistance mechanisms involving PI3K/PTEN and MAPK pathway co-alterations. A prospective FGFR-alt PDX biorepository enabled exploratory biomarker analyses, supporting the hypothesis that FGFR1-4 mRNA expression may better reflect FGFR dependency than genomic alterations alone. CONCLUSIONS: These findings highlight the complexity of FGFR-driven oncogenesis and support integrative molecular approaches to refine patient selection for FGFR-targeted therapies.