# Novel approaches to target KEAP1 mutant tumors

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $676,063

## 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. Loss of KEAP1
hyper-activates NRF2 and dramatically accelerates KRAS-driven LUAD. Furthermore, LUAD patients with
KEAP1 mutations do not respond to standard-of-care, including the recently approved KrasG12C inhibitors,
making this one of the most aggressive and hard to treat solid tumors. Building on our prior studies, we have
observed that KEAP1 mutant cells have an altered metabolism that can be therapeutically targeted. In this
application we focus on characterizing the molecular mechanisms and therapeutic potential of targeting the
polyol and fructolysis pathways by both genetic and pharmacological approaches in multiple KRAS-driven
KEAP1 mutant LUAD pre-clinical models. In addition, using newly established models of KrasG12C-mutant
LUAD with KEAP1 mutations we will determine the therapeutic potential of standard of care KrasG12C inhibitor
Sotorasib in combination with a KHK inhibitor that blocks fructolysis. Ultimately, our studies will provide a
rationale for inhibiting the fructolysis in KEAP1 mutant LUAD and support the sub-stratification of patients with
hyperactivation of the NRF2 pathway as treatment responders to therapies targeting the polyol and fructolysis
pathways, which is pertinent to the goals of precision medicine.

## Key facts

- **NIH application ID:** 10890983
- **Project number:** 1R01CA283049-01A1
- **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:** $676,063
- **Award type:** 1
- **Project period:** 2024-04-05 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890983

## Citation

> US National Institutes of Health, RePORTER application 10890983, Novel approaches to target KEAP1 mutant tumors (1R01CA283049-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890983. Licensed CC0.

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