411 Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis

Objectives/Goals: To investigate how distinct KRAS mutations (G12D, G12V, and G12R) drive distinct molecular and phenotypic programs in pancreatic tumorigenesis, linking early lineage and signaling differences to clinical patterns such as stage at diagnosis, nodal status, and survival to ultimately inform allele-specific therapies. Methods/Study Population: We analyzed clinical cohorts (MSK-IMPACT n=1,360; COMPASS n=100) and conducted lineage-tracing studies in mice carrying KRAS-G12D, KRAS-G12V, or KRAS-G12R alleles under inflammatory, genetic, and pharmacologic perturbations. Spatial transcriptomic and proteogenomic profiling of resected PDAC tissues characterized EMT and immune signaling states. Functional studies assessed EGFR–PI3K/AKT–RAC1/VAV1 signaling, including RAC1 inhibition and constitutive AKT activation, to reveal allele-specific susceptibilities. Results/Anticipated Results: KRAS-G12D drove robust lineage plasticity, enhancer remodeling, and early neoplastic progression. KRAS-G12R/V showed limited EMT and increased inflammatory signatures, with impaired EGFR–RAC1/VAV1 activation restricting lineage reversion. Constitutive AKT activation rescued the tumor-initiating defect of KRAS-G12R in vivo , pinpointing a downstream signaling bottleneck, which could be exploited therapeutically. Spatial and transcriptomic profiling of resected human PDAC revealed that KRAS-G12R tumors were more often early-stage, node-negative, and linked to improved survival relative to KRAS-G12D. Discussion/Significance of Impact: Integrating patient and mouse data reveals a mechanistic hierarchy among KRAS alleles that governs lineage fate, signaling reliance, and clinical course, pointing to opportunities for allele-tailored therapeutic strategies in pancreatic cancer.