# Ferroptosis resistance as a key driver in acquired radiation resistance

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $339,834

## Abstract

Project 1 Summary
Ferroptosis is a form of regulated cell death that is triggered by iron-dependent lipid
peroxidation. Previous studies by us and others identified ferroptosis as a critical tumor suppression
mechanism and suggested that inducing ferroptosis holds promise for cancer treatment. Recently, we and
others showed that radiotherapy (RT) can potently induce ferroptosis and identified ferroptosis inducers
(FINs) as radiosensitizers to tumors with intrinsic radioresistance (such as KEAP1 or p53 mutant tumors).
However, the mechanistic and therapeutic relevance of ferroptosis to acquired radioresistance remains
largely unexplored. Our long-term goals are to understand the mechanistic basis of ferroptosis in acquired
therapy resistance and to rationally target ferroptosis in acquired resistance and disease recurrence in
cancer treatment. The objectives of this application are to determine the mechanisms by which
ferroptosis resistance contributes to acquired radioresistance in thoracic cancers (including lung and
esophageal cancers), and to assess FINs as a therapeutic strategy to overcome acquired
radioresistance in these cancers. Our preliminary data support the central hypotheses that (i) ferroptosis
resistance represents a key mechanism underlying acquired radioresistance in lung and
esophageal cancers and (ii) combining FINs with immunotherapy is an effective therapeutic strategy to
overcome acquired radioresistance without causing significant damage to normal tissues. To test our
hypotheses, we will pursue the following specific aims: Specific Aim 1. To define the mechanisms by
which ferroptosis resistance drives acquired radioresistance. Specific Aim 2. To determine the
effectiveness of combining FINs with RT in overcoming acquired tumor radioresistance. Specific Aim 3. To
determine the potential effects of FINs on radiation-induced toxicity in normal cells and tissues. It is
expected that our proposed studies will identify novel mechanisms of ferroptosis and acquired radioresistance
and identify effective new therapeutic strategies to overcome acquired radioresistance in thoracic
cancer treatment. Our proposal is highly innovative because it focuses on previously unexplored
pathways linking ferroptosis to acquired radioresistance. Our proposed studies will have a significant
impact on both our understanding of the fundamental mechanisms of ferroptosis and therapy resistance
and our ability to target ferroptosis in acquired radioresistance in cancer treatment.

## Key facts

- **NIH application ID:** 10517143
- **Project number:** 1U54CA274220-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Boyi Gan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,834
- **Award type:** 1
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10517143

## Citation

> US National Institutes of Health, RePORTER application 10517143, Ferroptosis resistance as a key driver in acquired radiation resistance (1U54CA274220-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10517143. Licensed CC0.

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