# Targeting altered nitrogen metabolism in an aggressive subset of human lung cance

> **NIH NIH K22** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $197,082

## Abstract

PROJECT SUMMARY
Altered cellular metabolism is a hallmark of cancer as tumors rewire metabolic pathways to meet the
bioenergetic, biosynthetic, and redox requirements of malignant cells. Metabolic reprogramming is achieved
mainly by mutation of oncogenes and/or tumor suppressors. In non-small cell lung cancer (NSCLC), the most
prevalent form of lung cancer, oncogenic mutation of KRAS and loss of function mutation of STK11 (which
encodes the tumor suppressor LKB1) is particularly common (6-12%). This combination of mutations specifies
both aggressive oncological behavior and metabolic perturbation. It is my central hypothesis that this
concurrent mutation alters metabolic preferences in NSCLC, rendering mutant cells dependent on a suite of
enzymes and pathways. In support of this hypothesis, I recently discovered that KRAS/LKB1 co-mutant cells
share metabolomic signatures of perturbed nitrogen handling. In particular, KRAS/LKB1 co-mutants are
addicted to a urea cycle enzyme, carbamoyl phosphate synthetase 1 (CPS1). This enzyme produces
carbamoyl phosphate (CP) in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. The
selective dependence of KRAS/LKB1 co-mutants on CPS1, however, is not due to the canonical activity of the
enzyme. Instead, CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines.
CPS1 loss reduces the pyrimidine/purine ratio, induces DNA replication fork stalling and subsequent
DNA damage. With our previous studies as background, in this proposal, I will seek to understand the
mechanisms contributing to metabolic transformation in an aggressive subset of NSCLC. To this end, I will
pursue the following three specific aims: 1) to elucidate the mechanism and regulation of CPS1 addiction, 2) to
investigate the mechanism by which oncogenic KRAS mutation contributes to CPS1 addiction in KRAS/LKB1
co-mutants, and 3) to identify additional novel metabolic liabilities associated with nitrogen metabolism in
LKB1/KRAS co-mutants. My primary career goal is to obtain a tenure-track position in an academic setting at a
major U.S. university. My long-term goal is to build an independent research career as a cancer biologist with a
specific focus on metabolism. To achieve these goals, I hope to develop my intellectual knowledge base as
well as increase my technical skill repertoire throughout the duration of the proposed study. This training
should be readily attainable in the DeBerardinis laboratory at UT Southwestern Medical Center (UTSW); our
lab has expertise in the biochemical analysis and molecular dissection of complex metabolic pathways. In
order to promote and assure my progress during the K22 Award period, I have organized an advisory
committee consisting of internationally renowned scientists with expertise in different areas relevant to my
research and career goals. Collectively, the proposed studies will provide significant insight into mechanisms of
metabolic liability in cancer ...

## Key facts

- **NIH application ID:** 9868901
- **Project number:** 5K22CA226676-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jiyeon Kim
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $197,082
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868901

## Citation

> US National Institutes of Health, RePORTER application 9868901, Targeting altered nitrogen metabolism in an aggressive subset of human lung cance (5K22CA226676-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868901. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*