# Targeting ferroptosis in radioresistance in lung cancer: mechanisms and preclinical translation

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $385,437

## Abstract

Project Summary
 Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by excessive lipid
peroxidation. Previous studies by us and others identified ferroptosis as a natural tumor suppression mechanism
and showed that ferroptosis inactivation, like apoptosis inactivation, contributes to tumor development. Recently,
we and others also showed that radiotherapy (RT) can potently induce ferroptosis and suggested that ferroptosis
inducers (FINs) can be used in RT to overcome radioresistance. However, the underlying mechanisms of
ferroptosis in radioresistance and the exact cancer or genetic contexts in which to target ferroptosis in RT still
remain largely unexplored. This application aims to determine the mechanisms by which ferroptosis inactivation
contributes to radioresistance in KEAP1-mutant lung cancer cells and to assess the combination of RT and FINs
in treating KEAP1-mutant lung cancers. KEAP1 is commonly mutated in lung cancer, and KEAP1-mutant lung
cancers are resistant to RT. KEAP1 mutation or deficiency in lung cancer stabilizes NRF2 and promotes an
NRF2-mediated antioxidant response. Our recent publication and new preliminary data support our central
hypotheses that (i) KEAP1 deficiency promotes radioresistance largely through inhibiting ferroptosis, and KEAP1
regulates ferroptosis through NRF2 transcriptional targets SLC7A11 and other unidentified downstream targets;
and (ii) combining RT and FINs that inactivate SLC7A11 (or other potential ferroptosis inhibitors identified from
our studies) is an effective therapeutic strategy to overcome radioresistance in KEAP1-mutant lung cancers
without causing significant damage in normal tissues. To test our hypotheses, we will pursue the following
specific aims: Specific Aim 1: To determine the mechanisms by which KEAP1 regulates ferroptosis and
radioresistance in lung cancer cells. Specific Aim 2. To determine the effectiveness of combining FINs with RT
for treating KEAP1-mutant lung cancer. Our proposed studies are expected to identify novel mechanisms of
ferroptosis and radioresistance and to identify effective new therapeutic strategies to overcome radioresistance
in lung cancer treatment. Our proposed studies will have a significant impact on both our understanding of the
fundamental mechanisms of ferroptosis and radiation biology and our ability to target ferroptosis-related
radioresistance in cancer treatment.

## Key facts

- **NIH application ID:** 10312816
- **Project number:** 5R01CA247992-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Boyi Gan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,437
- **Award type:** 5
- **Project period:** 2020-12-07 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312816

## Citation

> US National Institutes of Health, RePORTER application 10312816, Targeting ferroptosis in radioresistance in lung cancer: mechanisms and preclinical translation (5R01CA247992-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10312816. Licensed CC0.

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