# Identifying metabolic dependencies in genetic subtypes of KRAS-driven lung cancer

> **NIH NIH R37** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $473,044

## Abstract

SUMMARY
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, and other cancers with hyperactivation of the NRF2 antioxidant
pathway. This application aims to: 1) Assess the therapeutic potential of inhibiting glutamine
utilization in both human and murine KRAS-driven LUAD models with KEAP1 mutations, 2)
Characterize the metabolic mechanisms underlying glutamine dependency in KEAP1 mutant
LUAD, and 3) Determine the therapeutic potential of inhibiting glutaminolysis in cancers with
hyperactivation of the NRF2 pathway. Our studies will provide a rationale for sub-stratification of
patients with hyperactivation of the NRF2 pathway as treatment responders to glutaminase
inhibitors, which is pertinent to the goals of precision medicine.
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## Key facts

- **NIH application ID:** 10104358
- **Project number:** 5R37CA222504-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Thales Papagiannakopoulos
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $473,044
- **Award type:** 5
- **Project period:** 2018-03-02 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104358

## Citation

> US National Institutes of Health, RePORTER application 10104358, Identifying metabolic dependencies in genetic subtypes of KRAS-driven lung cancer (5R37CA222504-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104358. Licensed CC0.

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