# NRF2-dependent redox signaling in pancreatic cancer

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $347,716

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy that remains largely incurable. The dismal
prognosis of PDA reflects its advanced disease stage at diagnosis and its profound resistance to existing
therapies. The KRAS oncogene is mutated in 95% of PDAs and acts as a potent driver of PDA growth and
maintenance. Oncogenic KRAS induces transcriptional upregulation of NFE2L2, which encodes the NRF2
transcription factor, a master regulator of redox homeostasis that protects cells from the cytotoxic/cytostatic
effects of reactive oxygen species (ROS). Importantly, we found that genetic ablation of NRF2 suppresses the
growth of pancreatic cancer cells both in vitro and in vivo (2). Although elevated levels of ROS are generally
believed to induce cytotoxicity through irreversible damage to macromolecules, particularly DNA and lipids, we
discovered that genetic ablation of NRF2 did not lead to DNA or lipid damage (2). Instead, both protein synthesis
and tumor cell fitness were compromised as a consequence of reversible and selective oxidation of cysteine
residues on key regulators of protein synthesis (2). Based on these observations, we hypothesize that NRF2
promotes pancreatic tumorigenesis through its ability to regulate oxidative post-translational
modifications (oxPTM). Herein, we propose to elucidate the mechanisms underlying this process, determine
the functions of redox control in PDA, and identify potential therapeutic targets. To this end, we will use ChIP-
seq and RNAseq to identify direct Nrf2 targeting genes that govern cysteine oxidative modification (Aim 1). In
addition, we will use a variety of biochemical approaches to delineate the mechanisms through which cysteine
oxidation contributes to protein synthesis in PDA. We will further define transcript-specific effects of redox-
dependent translation regulation through ribosome profiling (Aim 2). In addition to cysteine, we recently
discovered that perturbation of NRF2 activity also leads to the reversible oxidation of the other sulfur-containing
amino acid, methionine. Various biochemical and genetic approaches will be taken to assess the functional role
of methionine oxidation in pancreatic tumorigenesis (Aim 3). We anticipate that our results will explain
fundamental aspects of redox homeostasis in PDA and will inform the development of more effective therapies
for pancreatic cancer and potentially other KRAS-driven malignancies.

## Key facts

- **NIH application ID:** 10793486
- **Project number:** 5R01CA240654-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Christine Iok In Chio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $347,716
- **Award type:** 5
- **Project period:** 2020-03-04 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793486

## Citation

> US National Institutes of Health, RePORTER application 10793486, NRF2-dependent redox signaling in pancreatic cancer (5R01CA240654-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10793486. Licensed CC0.

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