# Defining the contributions of WT RAS in RAS-mutant lung cancer

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $68,562

## Abstract

Project Summary/Abstract
The three RAS genes (KRAS, NRAS, and HRAS) encode four highly identical (~90% sequence identity) proto-
oncogenes. Together they represent the most commonly mutated oncogene family in human cancers, mutated
in ~25% of all cancers. However, the mutational frequency of each RAS gene is unique among different cancer
types. Mutations in KRAS are most prevalent in pancreatic cancer (97% KRAS, 0% NRAS, 0% HRAS),
whereas NRAS is predominantly mutated in melanoma (1%, 28%, 1%, respectively), and HRAS in bladder
cancer (3%, 1%, 6%, respectively). This suggests that each RAS gene drives biological differences within
various cancer types. Additionally, recent studies have reported that the non-mutated, wild type (WT)
counterparts in mutant (MT) RAS-driven cancers can have tumor driver activities. These findings are
confounding, because in the context of MT RAS-driven cancers, WT RAS proteins are largely considered
“inactive”. These observations suggest that the WT and MT RAS proteins either play distinct roles or simply
have additive activities. I propose to test the roles of the WT and mutated RAS proteins in human lung
adenocarcinoma (LAC) cell lines, the leading cause of cancer deaths, where mutations in RAS proteins
account for 32% of all cases. I will use cell lines that are both MT KRAS (mutated in 31% of LAC) and MT
NRAS (mutated in 1% of LAC) driven. I hypothesize that the different mutational frequencies between the
KRAS and NRAS isoforms will be based on different biological activities in LAC. Furthermore, I expect to
identify unique mechanisms that correlate with specific WT and MT RAS isoforms and contribute to
oncogenesis. My preliminary data show that the suppression of both WT and MT RAS isoforms inhibits the
growth of LAC cancer cells and imparts differential signaling through downstream effectors. I propose three
aims to investigate the roles of WT and MT RAS isoforms in LAC. In aim 1, I will determine if WT and MT RAS
isoforms impact the growth of LAC cells in vitro using both 2D and 3D models, and in vivo within subcutaneous
xenografts. In aim 2, I will define the metabolic dependencies of each RAS isoform, namely their impact on
autophagic flux, macropinocytosis, mitochondrial function, glycolysis and respiration. Finally, in aim 3, I will
identify compensatory mechanisms that allow cells to overcome their addiction to WT and MT RAS. These
studies will provide key mechanistic insights as to how MT and WT RAS signaling works in concert to drive
oncogenesis in LAC. Thus, these studies will address important issues within the RAS field.

## Key facts

- **NIH application ID:** 10070586
- **Project number:** 5F32CA232529-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Clint A Stalnecker
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,562
- **Award type:** 5
- **Project period:** 2019-01-02 → 2022-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070586

## Citation

> US National Institutes of Health, RePORTER application 10070586, Defining the contributions of WT RAS in RAS-mutant lung cancer (5F32CA232529-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10070586. Licensed CC0.

---

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