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 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. METHODS: 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 FGFRi was observed in cases with FGFR mRNA over-expression 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 FISH. RNA sequencing identified a higher prevalence of FGFR mRNA over-expression than proteomic analysis. Among patients harboring FGFR-mut, only one bladder cancer with a 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. CONCLUSION: These findings highlight the complexity of FGFR-driven oncogenesis and support integrative molecular approaches to refine patient selection for FGFR-targeted therapies.