# Epigenetic mechanisms of gemcitabine resistance in pancreatic cancer

> **NIH NIH F31** · GEORGETOWN UNIVERSITY · 2021 · $33,336

## Abstract

Project Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal neoplasm in the US with 5-
year-survival rate of 8.5%. Currently, gemcitabine single agent or combination chemotherapies
remain the most commonly used frontline treatment for locally invasive and metastatic PDAC.
However, most PDAC tumors are intrinsically resistant or quickly acquire resistance to
gemcitabine. Epigenetic reprogramming through changes in global DNA methylation or histone
modification have been implicated in chemoresistance. Here, I established a model for
gemcitabine resistance progression in PDAC and identified a cytostatic transition phase prior to
regrowth under gemcitabine treatment. Through a small-molecule epigenetic inhibitor screen, I
identified PRMT1 (H4R3 arginine methyltransferase) and KMT2A/B (H3K4 lysine
methyltransferase) as positive and negative regulators of transition into gemcitabine resistance,
respectively. Based on these findings, I hypothesize that PDAC cells transition into gemcitabine
resistance through epigenetic reprogramming that is in part mediated by PRMT1 and KMT2A/B.
In Aim 1, I will functionally validate PRMT1 and KMT2A/B in modulating PC gemcitabine
resistance in vitro and in vivo. In Aim 2, I will investigate the mechanisms by which PRMT1 and
KMT2A/B modulate gemcitabine resistance through integrated genomic analysis. Collectively, I
expect my study will shed important new insight into the mechanisms of gemcitabine resistance
in PDAC, which could lead to novel combination therapies to enhance the efficacies and durability
of gemcitabine in PDAC.

## Key facts

- **NIH application ID:** 10071870
- **Project number:** 5F31CA247417-02
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Chan D Nguyen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,336
- **Award type:** 5
- **Project period:** 2019-12-10 → 2022-12-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071870

## Citation

> US National Institutes of Health, RePORTER application 10071870, Epigenetic mechanisms of gemcitabine resistance in pancreatic cancer (5F31CA247417-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10071870. Licensed CC0.

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