Abstract A027: Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis

Abstract Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic cancer (PDAC). How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRASG12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRASG12R/V can initiate but not sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. We find the KRASG12R/V defects consist of a failure to invoke robust EGFR signaling and an inability to drive the transcription and epigenetic remodeling of the key tuft cell transcription factor Pou2f3 and the RAC1 GEF Vav1. These in turn lead to a defect in RAC1 signaling and downstream remodeling of the actin cytoskeleton critical to pancreatic intraepithelial neoplasia (PanIN) development. To address the contexts in which KRASG12R could give rise to robust tumorigenesis, we incorporated genetic and pharmacologic perturbations in vivo to inactivate one or two copies of p53, to modulate MAPK/ERK signaling, or to enforce active RAC1. Whereas none of these models could enforce KRASG12R-driven tumor initiation, we found that only constitutive AKT activation in vivo was sufficient to rescue both RAC1 signaling and the tumorigenic potential of KRASG12R. Corroborating these findings, we observe in the human context an enrichment of PI3K pathway mutations specifically in KRASG12R-mutant PDAC. These data underscore that lineage plasticity is facilitated by all three Kras mutants but neoplastic commitment depends significantly on the precise mutation in Kras. As the marked heterogeneity among KRAS variants begins early in tumorigenesis, our findings are crucial in delineating there are mutation-specific oncogenic trajectories that should in turn direct the implementation of KRAS-directed therapeutics and early detection strategies in patients. Citation Format: Adrien Grimont, David J. Falvo, Whitney J. Sisso, Paul Zumbo, Francisco Santos, Christopher W. Chan, William B. Fall, Grace Pan, Yinuo Meng, Katherine Ferrick, Megan Cleveland, Maria Paz Zafra, Tomer M. Yaron, Andre F. Rendeiro, Erika Hissong, Rhonda K. Yantiss, Doron Betel, Mark A. Magnuson, Steven D. Leach, Anil K. Rustgi, Lukas E. Dow, Rohit Chandwani. Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A027.