# Project 3: Targeting KEAP1-Mediated Radioresistance in Lung Cancer

> **NIH NIH P01** · STANFORD UNIVERSITY · 2022 · $380,631

## Abstract

Abstract (Project 3)
Radiation therapy (RT) plays a critical role in the treatment of non-small cell lung cancer (NSCLC). While
advances in tumor imaging and radiation delivery techniques have significantly improved RT, advances in
genomic and molecular understanding of tumors have largely failed to impact management of patients treated
with RT. Therefore, development of “precision radiation oncology” approaches, defined as the use of molecular
biomarkers to personalize RT, remains a major unmet need. Our long-term goal is to develop novel,
molecularly-based precision radiation oncology approaches for NSCLC patients treated with RT. We previously
demonstrated that NSCLCs with KEAP1 or NFE2L2 mutations are radioresistant and have high rates of local
recurrence after RT. In this proposal we will develop a personalized radiosensitization strategy for
KEAP1/NFE2L2 mutant tumors based on inhibition of glutaminase, which plays a critical role in biosynthesis of
cellular free radical defenses. Prior studies have found conflicting results regarding the ability of glutaminase
inhibition to radiosensitize NSCLC. Our central hypothesis is that glutaminase inhibition can radiosensitize
KEAP1/NFE2L2 mutant but not wildtype NSCLCs and if correct would help explain the previous conflicting
results. We will therefore test if our genotype-specific radiosensitization approach has efficacy in KEAP1/NFE2L2
mutant but not wildtype NSCLC in vivo. We will also test if our approach increases normal tissue toxicity.
Additionally, we will identify specific KEAP1 mutations that cause radioresistance in order to enable identifying
patients with radioresistant tumors. In collaboration with Project 1, we will also test if the complement inhibitor
PMX205 can serve as an additional radiosensitizer for KEAP1/NFE2L2 mutant NSCLC. Finally, in collaboration
with Project 2 we will test if glutaminase inhibition can radiosensitize NFE2L2-mutant head and neck cancers.
If successful, our project will establish glutaminase inhibition as a precision radiation oncology strategy for
personalized radiosensitization of KEAP1/NFE2L2 mutant NSCLC. This approach could widen the therapeutic
index of RT since it would only expose patients at highest risk of local recurrence to the potential additional
toxicities of adding a radiation sensitizer. Our results will serve as the basis for developing clinical trials to attempt
to translate this strategy. These trials will involve genotyping of NSCLC patients undergoing RT in order to select
patients with KEAP1/NFE2L2 mutations for concurrent treatment with RT and glutaminase inhibitors. Importantly,
our findings will serve as proof-of-principle that can likely also translate to other tumor types with frequent
KEAP1/NFE2L2 mutations.

## Key facts

- **NIH application ID:** 10334201
- **Project number:** 1P01CA257907-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Maximilian Diehn
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,631
- **Award type:** 1
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334201

## Citation

> US National Institutes of Health, RePORTER application 10334201, Project 3: Targeting KEAP1-Mediated Radioresistance in Lung Cancer (1P01CA257907-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10334201. Licensed CC0.

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