Distinct multi-omic signatures that underlie KRAS variants and survival in KRAS G12R pancreatic cancer.

4234 Background: KRAS mutations are the dominant oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). While KRAS G12D/V variants are associated with aggressive disease and poor prognosis, the biological basis for survival differences among KRAS variants remains incompletely defined. We leveraged a comprehensive multi-omics dataset to characterize variant-specific molecular signatures associated with survival. Methods: Tissue and plasma samples from 72 patients with Stage I/II resectable PDAC were retrospectively analyzed using the Aseesa Stars multi-modal integrated platform. Multi-omic profiling included targeted DNA sequencing, whole-transcriptome RNA sequencing, tissue and plasma proteomics, lipidomics, and computational pathology, generating 6,363 features linked to overall survival (OS). Analyses focused on KRAS wild-type (n=7) and the most prevalent KRAS variants: G12R (n=12), G12D (n=21), and G12V (n=13). Results: Patients with KRAS G12R who underwent upfront resection demonstrated significantly longer OS compared with G12D/V variants (median OS 37.5 vs. 18.9 months; HR 0.50 95% CI 0.23–1.09; log-rank p=0.047). Compared with KRAS-WT, combined KRAS-mutant tumors exhibited significant alterations in neutrophil degranulation, apoptosis, protein transport, cell adhesion, and oxidative phosphorylation (OXPHOS) pathways (p<0.05). A total of 381 molecular signatures differed significantly (p<0.05) between G12R and G12D/V cohorts. In direct G12R vs. G12D comparison, 110 features were unique to high OS (p<0.05). KRAS G12R, G12D and G12V shared activation of PI3K/AKT, MET, and PTPN11 signaling, consistent with a common aggressive phenotype. In contrast, KRAS G12R tumors demonstrated significant alterations in major mRNA splicing and OXPHOS pathways (p<0.05). Splicing regulators PLRG1 and RBM8A were reduced in G12R patients by 6% (p<0.03). Six OXPHOS-related signatures also favored high OS, lipid hexosylceramide 24:1 was decreased by 14.59% (p=0.016). Tissue protein ACADS decreased by 5.38% (p=0.025) in G12R high OS, but increased in G12D high OS. Conclusions: KRAS G12R defines a molecularly distinct PDAC subtype with improved survival, characterized by suppressed mRNA splicing signatures and coordinated metabolic remodeling, highlighting variant-specific metabolic and molecular divergence. These findings underscore the importance of KRAS variant stratification for prognostication and future development of variant-specific precision therapeutic strategies.