Date of Award

Summer 8-7-2025

Embargo Period

7-29-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

G. Aaron Hobbs

Second Advisor

Robin Muise-Helmericks

Third Advisor

John P. O'Bryan

Fourth Advisor

Nathan Dolloff

Fifth Advisor

Mindy Engevik

Sixth Advisor

Micheal Owstroski

Abstract

In pancreatic ductal adenocarcinoma (PDAC), ~95% of cases harbor an activating KRAS mutation. The most common KRAS mutations in PDAC are KRASG12D (42%), KRASG12V (31%), and KRASG12R (15%). Patients harboring KRASG12R mutations have increased overall survival compared to those with KRASG12D/V-mutations. While KRASG12D/Vare common in all KRAS-mutant cancers, KRASG12Ris only common in PDAC.

KRASG12R is unable to activate the lipid kinase PIK3CA, a KRAS effector that is important for tumorigenesis in murine models. To investigate the tumorigenic potential of KRASG12R and the mechanisms that enable this mutation to drive PDAC, we developed both pancreas-specific and whole-body KRAS-mutant genetically engineered mouse models (GEMMs). Unlike their KrasG12D counterparts, KrasG12R-mutant mice exhibited extremely limited tumorigenesis. Using murine and human PDAC cell lines, GEMMs and patient-derived xenograft mouse models we showed that KRAS is not the primary driver of PI3K activity in human PDAC regardless of specific KRAS mutation. Overall, KRASG12R and KRASG12D activate a similar pancreas-specific transcriptional network, but KRASG12R promotes these pathways less robustly, due to limited activation of WT RAS isoforms and reduced ERK nuclear translocation. Additionally, KRASG12R-pancreatic tumors have an altered tumor microenvironment with reduced collagen deposition and metastatic liver invasion.

Further investigation of KRAS-independent mechanisms of PI3K activation revealed that PTEN, the negative regulator of PI3K signaling, is inactivated in PDAC through a redox-mediated modification that supports elevated basal PI3K signaling. All four PI3K Class I isoforms contribute to global PI3K signaling, and inhibition of any single isoform is insufficient to limit PDAC proliferation. Using proximity labeling alongside RNA sequencing analysis, we mapped early effector interactions of common and rare KRAS mutations to show that pancreatic cells are highly tolerant to overexpression of common mutations, but overexpression of the rare, constitutively active KRASQ61L leads to impaired proliferation and increased apoptosis through hyperactivation of the ERK/MAPK pathway. Overall, these findings reveal key mechanisms of KRAS-independent PI3K activation, define the role of KRAS-driven global ERK/MAPK signaling in determining oncogenic potential, and underscore the need for dual targeting of KRAS and PI3K/AKT pathways in pancreatic cancer.

Rights

Copyright is held by the author. All rights reserved.

Download

Available for download on Wednesday, July 29, 2026

Share

COinS