# Project 3: Mechanisms and therapeutic targeting of NRAS in melanoma

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $143,966

## Abstract

ABSTRACT 
Much remains to be learned about how RAS isoforms differ functionally from each other, and about the impact 
of specific mutations on each RAS protein. NRAS-mutant melanoma represents both a critical unmet need in 
terms of efficacious therapeutic options and also an outstanding opportunity to elucidate these functional 
differences. Although KRAS is the predominant RAS isoform mutated in cancers overall, NRAS is the 
predominant RAS isoform mutated in malignant melanoma, and whereas mutations at codon 61 are rare in 
KRAS, they predominate in NRAS. Project 2 has recently demonstrated that Nras Q61R but not G12D could 
drive melanoma formation in Ink4a-deficient mice. These provocative findings indicate that NRAS Q61R and 
G12D must activate distinct effectors, and/or activate effectors in a distinct manner. Given the preferential 
occurrence of NRAS Q61 mutations in melanoma, we propose studies to elucidate the signaling mechanisms 
that distinguish the roles of Q61- versus G12-mutant NRAS in driving these cancers. We hypothesize that 
there are structural, biochemical and biological properties distinct from those of the more common G12-mutant 
KRAS proteins found in lung, colorectal and pancreatic carcinomas. We have also identified an unexpected 
requirement for both KRAS and HRAS WT forms in NRAS-mutant melanomas. We will investigate effector 
signaling mechanisms driven by different NRAS mutants, define the requirements for WT isoforms, and 
leverage both candidate- and unbiased methodologies to identify targets that can lead to novel combination 
therapies for effective treatment of NRAS-driven melanomas. To address our goals, we propose three aims. In 
Aim 1, we will elucidate known and unknown effector signaling pathways downstream of cellular NRAS 
mutated at codon 61 versus codon 12. This Aim will be performed in close collaboration with Project 2, which 
will focus on structural and biochemical differences in the same panel of NRAS mutants. Projects 1 and 4 will 
also examine some of the cellular and tumorigenic phenotypes of the same mutations in different RAS 
isoforms. In Aim 2, we will characterize the requirement for WT RAS isoforms, and determine functional 
differences in effectors and signaling networks, as well as in transformed growth properties. In Aim 3, we will 
determine whether the same mechanisms that overcome melanoma addiction to mutant NRAS also overcome 
dependency on WT RAS isoforms. To do this, we will first interrogate YAP, known to be capable of rescuing 
addiction to mutant KRAS in carcinomas, and we will next perform a novel functional genetic screen to identify 
non-YAP mechanisms in an unbiased manner. Collectively, our studies will elucidate a better understanding of 
the neglected NRAS isoform, characterize functional distinctions among different NRAS mutations, determine 
relationships between WT and mutant NRAS-driven effector signaling pathways and networks, and identify 
new directions for no...

## Key facts

- **NIH application ID:** 9982073
- **Project number:** 5P01CA203657-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** ADRIENNE D COX
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $143,966
- **Award type:** 5
- **Project period:** — → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982073

## Citation

> US National Institutes of Health, RePORTER application 9982073, Project 3: Mechanisms and therapeutic targeting of NRAS in melanoma (5P01CA203657-05). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/9982073. Licensed CC0.

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