# Project 2: Role of codon and isoform differences in Ras tumorigenesis

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $119,055

## Abstract

Project 2: Role of codon and isoform differences in RAS tumorigenesis 
Project Leader: Sharon L. Campbell 
Abstract: RAS genes encode small 21 kD GTPases that cycle between active and inactive states to regulate 
cellular growth. Approximately one-third of all human cancers contain activating mutations in RAS genes, with 
codon hotspots at positions 12, 13 and 61. These point mutations render RAS proteins insensitive to down 
regulation, resulting in chronic RAS activation and constitutive, oncogenic signaling. As such, they have 
historically been considered oncogenic equivalents. However, recent observations suggest that codon- and 
residue-specific RAS mutations differ in their ability to function as GTPases switches, engage effectors, and 
promote signaling and tumorigenesis. Differences have also been observed in the response and resistance to 
specific anti-cancer therapies. Thus understanding these differences will have important clinical and biological 
implications. It is also intriguing that cancers display tissue-specific preferences in both RAS mutation and 
isoform type. To better understand cancer-specific RAS mutation and isoform differences, we propose 
structural and biochemical characterization studies on the KRAS and NRAS isoforms. These studies will be 
highly integrated with other components of the P01, and include cell-based and mouse studies to correlate 
molecular information with RAS activation levels, RAS-mediated signaling and tumorigenesis. In Aim 1, we will 
determine whether codon- and residue-specific oncogenic mutations in NRAS and KRAS differentially alter 
intrinsic RAS function and effector recognition. In Aim 2, we will determine whether sequence differences in 
the core GTPase domain of NRAS and KRAS drive isoform-specific differences in intrinsic RAS function, 
signaling and tumorigenesis. In Aim 3, we will determine how the activity and tumor promoting properties of 
KRAS and an oncogenic KRAS mutant (G12C) prevalent in lung cancer are regulated by cysteine oxidation. 
Characterization of the redox properties of KRAS G12C will aid in anti-cancer efforts to target this oncogenic 
mutant, as well as understanding distinct the phenotypes of KRAS G12C observed in cell-based and mouse 
model studies. The proposed studies will help elucidate codon-, residue- and isoform-specific differences that 
promote RAS-driven cancers, which will inform the development of new and more specific therapies to target 
aberrant RAS function in cancer.

## Key facts

- **NIH application ID:** 9982072
- **Project number:** 5P01CA203657-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Sharon L Campbell
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $119,055
- **Award type:** 5
- **Project period:** — → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982072

## Citation

> US National Institutes of Health, RePORTER application 9982072, Project 2: Role of codon and isoform differences in Ras tumorigenesis (5P01CA203657-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982072. Licensed CC0.

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