# Investigating the therapeutic potential of a novel glutamine antagonist in KEAP1 mutant lung cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $672,853

## Abstract

PROJECT SUMMARY/ABSTRACT
Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge for clinical oncology.
Approximately 20% of KRAS mutant LUAD tumors carry loss-of-function mutations in KEAP1, a negative
regulator of NRF2, which is the master transcriptional regulator of the endogenous antioxidant response. Using
CRISPR/Cas9-based somatic editing in a genetically engineered mouse model of KRAS-driven LUAD we
demonstrated that loss of Keap1 hyper-activates Nrf2 and dramatically accelerates KRAS-driven LUAD.
Combining CRISPR/Cas9-based genetic screening and metabolic analyses, we showed that Keap1 mutant cells
are dependent on increased glutamine metabolism, and this property can be therapeutically exploited through
the pharmacological inhibition. In this application we focus on characterizing the molecular mechanisms and
therapeutic potential of targeting glutamine metabolism in KRAS-driven KEAP1 mutant LUAD This application
aims to: 1) Assess the therapeutic potential of novel glutamine antagonist in both human and murine KRASG12D-
and KRASG12C-driven KEAP1 mutant LUAD pre-clinical models, 2) Provide a rationale for sub-stratification of
human lung cancer patients with KRAS-KEAP1 or -NRF2 mutant tumors as likely responders to glutamine
antagonists and determine the therapeutic potential of combining with clinically relevant KC-Is with DRP-104. 3)
Characterize the metabolic mechanisms underlying glutamine antagonist sensitivity in KRAS-driven KEAP1
mutant LUAD, and 4) Identify mechanisms of resistance to glutamine dependence. Our studies will provide a
rationale for sub-stratification of patients with hyperactivation of the NRF2 pathway as treatment responders to
DRP-104, a novel glutamine antagonist in clinical trials, which is pertinent to the goals of precision medicine.

## Key facts

- **NIH application ID:** 10803727
- **Project number:** 1R01CA262562-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Thales Papagiannakopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $672,853
- **Award type:** 1
- **Project period:** 2023-12-19 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803727

## Citation

> US National Institutes of Health, RePORTER application 10803727, Investigating the therapeutic potential of a novel glutamine antagonist in KEAP1 mutant lung cancer (1R01CA262562-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10803727. Licensed CC0.

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