KRAS Expression Complements Genomic Profiling in Identifying Therapeutic Vulnerability in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) remains a major therapeutic challenge. Although alterations in the RAS pathway occur in over 50% of tumors, only a limited proportion are clinically actionable. We investigated whether KRAS expression complements genomic profiling for patient stratification and therapeutic vulnerability in GC. METHODS: Comprehensive genomic profiling was performed in 19 Taiwanese GC patients and compared with TCGA-STAD data (n = 434). KRAS mRNA expression and overall survival were evaluated by meta-analysis of 13 independent cohorts (n = 2,521). Protein-level validation was performed by immunohistochemistry in an independent cohort (n = 121). Functional KRAS dependency and response to combined MEK/SHP2 inhibition were assessed in eight GC cell lines. RESULTS: KRAS amplification was entirely contained within the KRAS-high population, whereas most KRAS-high tumors lacked detectable amplification. High KRAS expression was associated with poorer overall survival (HR 1.23, p = 0.001) and remained an independent prognostic factor after multivariable adjustment (adjusted HR 1.24, p = 0.003). Protein-level analysis showed a concordant trend. KRAS expression correlated strongly with functional dependency (R2 = 0.88, p = 0.005), was enriched in MSI and CIN subtypes, and identified cell lines with enhanced sensitivity to combined MEK/SHP2 inhibition. CONCLUSIONS: KRAS expression complements genomic profiling by identifying biologically relevant KRAS-dependent GCs beyond mutation or amplification alone. Integrating expression-based stratification with genomic profiling may improve patient selection for RAS pathway-directed combination therapies.