# Defining Novel Redox Stress Mechanisms to Inhibit KRAS-driven Pancreatic Ductal Adenocarcinoma

> **NIH NIH F31** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $48,974

## Abstract

Project Summary
 Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths with a 5-year survival
rate of 12%. Over 90% of PDAC is driven by oncogenic KRAS, however inhibitors targeting KRAS have been
unsuccessful in the clinic thus far. Targeting oncogenic vulnerabilities is a key alternative approach. Oncogenic
RAS-generated reactive oxygen species (ROS) drives tumor progression through hyperactivation of proliferative,
anti-apoptotic, and metastatic pathways. However, ROS can also trigger tumor suppressive outcomes through
cellular damage. The nucleotide pool-cleansing 8-oxo-dGTPase MutT Homolog 1 (MTH1) is a critical redox
protective adaptation in RAS-driven tumor cells to overcome tumor-inhibitory ROS mediated consequences.
MTH1 has been shown to prevent oncogene-induced oxidative stress and damage, and maintain high KRAS
oncoprotein expression, associated ROS-driven oncogenic signaling, and tumorigenicity in lung cancer. Given
the importance of MTH1 in KRAS oncogenic biology and the fact that over 90% of PDAC is driven by oncogenic
KRAS, I propose that MTH1 is similarly important in PDAC. In support of this idea, TCGA analysis revealed
MTH1 expression is significantly higher in tumor tissue compared to normal tissue, and high MTH1 significantly
correlates with poor disease-free survival. The Rai lab reported 8-oxodGTPase activity is significantly elevated
in patient PDAC tumor vs. normal tissue. Preliminary data show MTH1 loss reduces tumor burden in a subset of
PKT cohorts, with lower burden associated with both reduced intratumoral EGFR expression and in cytokines
associated with an immunosuppressive tumor microenvironment (TME). When MTH1 is depleted via shRNA in
PDAC cell lines, there is a significant decrease in proliferation associated with decreased total EGFR. Analysis
of human PDAC tumor data through TIMER 2.0 shows intratumoral MTH1 expression significantly correlates
with infiltration of myeloid derived suppressor cells (MDSCs), suggesting high MTH1 expression supports and/or
creates the immunosuppressive TME that make PDAC so difficult to treat. Therefor I hypothesize MTH1 is
important for PDAC tumorigenesis through both tumor cell-intrinsic as well as previously-unappreciated
extrinsic mechanisms. To test this hypothesis, I will use our novel PKT mouse models with systemic and
pancreas-specific MTH1 loss. Experiments proposed in Aim 1 will assess how systemic vs pancreas-specific
MTH1 loss affects in vivo KRAS tumorigenesis; Aim 2 will independently ascertain how MTH1 regulates KRAS-
driven transformation and PDAC chemoresistance. Upon completion of these studies, we will establish novel
mechanisms by which MTH1 regulates tumorigenesis thus filling a gap in the field regarding the link between
MTH1 and KRAS in PDAC. Lastly, these aims have the potential to validate MTH1 as an alternative to targeting
oncogenic KRAS in PDAC patients which has been unsuccessful to date.

## Key facts

- **NIH application ID:** 10825261
- **Project number:** 1F31CA288141-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Beatriz Mateo-Victoriano
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825261

## Citation

> US National Institutes of Health, RePORTER application 10825261, Defining Novel Redox Stress Mechanisms to Inhibit KRAS-driven Pancreatic Ductal Adenocarcinoma (1F31CA288141-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10825261. Licensed CC0.

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