# Defining Mutation-Specific NRAS Functions in Melanoma

> **NIH NIH F31** · OHIO STATE UNIVERSITY · 2020 · $38,466

## Abstract

PROJECT SUMMARY (ABSTRACT)
NRAS-mutant cutaneous melanoma is the most aggressive genetic subtype of this disease and has the worst
overall prognosis. While NRAS is one of the most commonly mutated genetic drivers of cutaneous melanoma,
drugs that effectively target mutant NRAS have yet to be developed. For decades, NRAS has been touted as
an ‘undruggable’ oncogene because the protein lacks a traditional, deep drug binding pocket. Furthermore,
therapies targeting post-translational modifications, interacting partners, and signal transduction pathways
downstream of NRAS are invariably circumvented by oncogenic variants. Mutations in NRAS primarily alter
codons 12, 13, and 61, leading to constitutive protein activation and signaling. However, there appears to be a
preference for specific NRAS alterations in each human tumor type. For example, NRAS-mutant melanomas
are enriched for genetic alterations in codon 61 (>80%) while acute myeloid leukemias exhibit a preference for
mutations affecting codons 12 and 13. This mutational bias remains poorly understood, especially in
melanoma where codon 61 alterations cannot be attributed to ultraviolet light. I hypothesize that only NRAS
oncogenes found commonly in melanoma (Q61 -R, -K, and -L) possess the functional properties
required to efficiently drive melanoma formation. To test this hypothesis, I generated a suite of conditional,
NRas knock-in mice (LSL-Q61R, -K, -L, -H, -P, and –Q; LSL-G12C and –D; LSL-G13D and -R) and crossed
these animals to a melanocyte-specific Cre. Preliminary data from a subset of these genetically engineered
mouse models (GEMMs) indicate that the melanomagenic potential of each NRas allele parallels the frequency
of that allele in human melanoma. Here, I will employ our full suite of knock-in GEMMs to elucidate the
melanomagenic potential of these ten, distinct NRas oncogenes (Aim 1). Capitalizing on these results as well
as our preliminary data, preferential effector usage amongst NRas mutants will be explored using BioID (Aim
2). Furthermore, in vitro transcriptomic and phosphoproteomic analyses employing melanocytes isolated form
these GEMMs will identify mutation-specific alterations in NRas signaling required for melanoma formation
(Aim 3). Completion of these aims will identify melanoma-specific tumor vulnerabilities downstream of
oncogenic NRAS and enhance our understanding of the evolution of this challenging disease.
To advance my development as an independent scientist I have generated a comprehensive training plan
including, but not limited to the following activities: oral presentations, scientific writing, undergraduate
mentoring, multi-dimensional data analysis, instruction in murine tumor pathology, external collaborations, and
Responsible Conduct in Research training. Presentations at project-relevant meetings and interactions with my
dissertation committee will foster feedback from the scientific community to enhance the long-term impact of
this work.

## Key facts

- **NIH application ID:** 9859191
- **Project number:** 5F31CA236418-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Brandon M. Murphy
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,466
- **Award type:** 5
- **Project period:** 2019-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859191

## Citation

> US National Institutes of Health, RePORTER application 9859191, Defining Mutation-Specific NRAS Functions in Melanoma (5F31CA236418-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9859191. Licensed CC0.

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