Integrative Proteogenomic and Single-Cell Analysis Reveals RTK Switching and Metabolic Reprogramming as Synthetic Lethal Vulnerabilities in FGFR Inhibitor Resistance

Background Although fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) have demonstrated clinical promise, the inevitable emergence of acquired resistance remains a distinct bottleneck, severely compromising their long-term clinical efficacy. The pan-cancer molecular landscape and heterogeneous mechanisms driving this resistance, ranging from genetic alterations to dynamic network rewiring, remain poorly understood. Methods We integrated large-scale pharmacogenomic profiling (GDSC2 and PRISM) with single-cell RNA sequencing to dissect the proteogenomic landscape of FGFRi resistance across 312 cell lines from 8 cancer types, complemented by machine learning modeling and systematic synthetic lethality screening to uncover actionable therapeutic targets. Results Our dual-database analysis unveiled a multi-dimensional atlas of FGFRi resistance. We identified cancer-specific genomic drivers, such as ELF4 amplification in glioblastoma, alongside key transcriptomic markers including UCP2 and FSCN1 , highlighting a shift towards metabolic reprogramming and epithelial-mesenchymal transition (EMT). Single-cell resolution analysis unveiled that resistance is predominantly associated with the enrichment of subpopulations harboring aberrant cell-cycle dysregulation (MP2), suggesting a model of clonal selection rather than purely transcriptional plasticity-driven adaptation. Furthermore, a Random Forest model based on 52 mRNA features was constructed, demonstrating robust predictive capability for FGFRi sensitivity (AUC > 0.7). Most notably, our synthetic lethal screening revealed a convergent reliance on compensatory RTK signaling (specifically EGFR pathway enrichment) and downstream MAPK/PI3K cascades in resistant phenotypes, providing robust evidence for an "RTK switching" mechanism. Conclusions This study establishes a high-resolution proteogenomic atlas of FGFRi resistance, identifying a convergent evolution towards metabolic reprogramming and EGFR-mediated bypass signaling. Our findings characterize resistance as a dynamic network rewiring and propose rational combination therapies (e.g., FGFRi combined with EGFR or metabolic inhibitors) to overcome resistance.