# Redox Modification and Targeting of Mutant KRas in Cancer

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $193,808

## Abstract

ABSTRACT
Oncogenic mutation of KRAS is a signature event in progression and growth of pancreatic cancer, an almost
universally fatal disease. Oncogenic KRAS allele expression leads to metabolic changes and altered cellular signaling
pathways that both stimulate the production of intracellular reactive oxygen species (ROS). Increases in ROS drive
formation and progression of pancreatic precancerous lesions by upregulating survival and growth factor signaling
pathways. Despite ROS dysregulation being central to cancer cell proliferation, as exemplified by KRas-induced
tumorigenesis, the mechanisms underlying ROS-dependent neoplasia remain very poorly understood. Elucidation
and characterization of the redox-dependent ‘switches’ that support ROS-driven neoplasia have been severely
hampered by the lack of direct methods to examine oxidative cysteine modifications in their native cellular
environment. Our laboratory has addressed this challenge through the development of a chemoproteomic approach
for in situ detection of the prototypical protein biomarker of redox signaling and stress, known as cysteine sulfenic acid
(Cys-SOH or S-sulfenylation). Here, we apply state-of-the-art methods to accomplish our major objectives of: 1) site-
specific mapping and characterization of KRasmut-dependent cysteine-based redox ‘switches’ that support
development of pancreatic cancer, and 2) examining the tumorigenic potential and pharmacological impact of
oxidative modification at the acquired cysteine in mutant KRasG12C. Successful completion of this project will identify
oxidative cysteine modification as an integral feature of processes that initiate pancreatic cancer through mutant KRas.
It will also delineate the relationship between oxidative modification of the redox-active thiol of KRasG12C to its
tumorigenic potency and the efficacy of small-molecules designed to target this mutant. It will also define the role of
redox in tumorigenic potency of KRasG12C and the efficacy of small-molecules designed to target this mutant. In
addition to KRas itself, the molecular components of redox pathways identifying during this study may represent
new biomarkers and drug targets for the early diagnosis and treatment of pancreatic cancer.

## Key facts

- **NIH application ID:** 10595875
- **Project number:** 6R01CA227849-05
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Kate Suzanne Carroll
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,808
- **Award type:** 6
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10595875

## Citation

> US National Institutes of Health, RePORTER application 10595875, Redox Modification and Targeting of Mutant KRas in Cancer (6R01CA227849-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10595875. Licensed CC0.

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