# Targeting Heme Metabolism for the Treatment of KRAS- KEAP1-Mutant Lung Adenocarcinoma

> **NIH NIH F30** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $51,752

## Abstract

Project Abstract
 KRAS-driven lung adenocarcinoma (LUAD) represents a major non-small cell lung cancer (NSCLC)
genetic subtype for which treatment options remain limited. Mutations in the KEAP1/NRF2 signaling pathway
are common events in several solid cancers, including KRAS-driven LUAD, and are associated with poor patient
prognosis and outcomes. KEAP1 loss of function (LOF) triggers stabilization of the transcription factor NRF2
which leads to dramatic metabolic and antioxidant reprogramming that confers proliferative and survival
advantages to tumor cells. However, these selective advantages also confer targetable metabolic dependencies
which arise specifically in the context of KEAP1/NRF2 mutations. The enrichment of these mutations in LUAD
carrying undefined or untargetable driver mutations makes unmasking therapeutic vulnerabilities particularly
urgent. Identifying metabolic liabilities within KRAS-mutant LUAD would enable the application of precision
medicine for the improvement of patient outcomes.
 In this proposal, I present findings which suggest Keap1-mutant tumors show increased sensitivity to
disruption of heme synthesis and that this phenotype is due to Nrf2 activation. I outline my proposed approach
to interrogate the metabolic and genetic underpinnings of this apparent vulnerability. I then describe how I will
assess if this pathway shows potential for targeted therapy in preclinical models of Kras-driven LUAD including
the use of genetically engineered mouse models of LUAD.
 Hypomorphic mutations in nearly all heme synthesis enzymes have been reported to cause some form
hereditary hepatic porphyria. Despite the potential severity of these diseases, their existence among the general
population, including healthy adults, provides evidence for the existence of a therapeutic window for heme
synthesis inhibition for the treatment of cancer. This fellowship application aims to uncover a novel metabolic
target in this genetic subtype of LUAD and will yield a better understanding of a fundamental, yet understudied,
metabolic pathway in the development of lung cancer.

## Key facts

- **NIH application ID:** 10405424
- **Project number:** 5F30CA247020-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Warren Wu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405424

## Citation

> US National Institutes of Health, RePORTER application 10405424, Targeting Heme Metabolism for the Treatment of KRAS- KEAP1-Mutant Lung Adenocarcinoma (5F30CA247020-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405424. Licensed CC0.

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