# Targeting Rheostatic Mechanisms of Melanoma Progression

> **NIH NIH R37** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $348,844

## Abstract

Cutaneous melanoma is highly lethal and the fifth most common cancer in the U.S. Peak incidence is in middle
age adults but the elderly, young adults and even children are affected. Among all cancer types, melanoma is
one of the most aggressive in its propensity for extremely early metastasis. Metastatic melanoma is difficult to
eradicate and new therapies are urgently needed to limit disease progression. Genetic causes of melanoma
align along a continuum of RAS protein signaling whereby BRAFV600E mutation is the most common driver. The
mutant BRAFV600E protein depends on MAPK signaling for both initiation and maintenance of tumor growth.
Targeting this abnormally-activated pathway with RAF and MEK inhibitors have had limited success in treating
this disease due to MAPK signaling reactivation, causing drug resistance. Thus, more mechanistic insights are
needed in order to develop combination therapies that can circumvent resistance. We reported that aberrant
activation of the small GTPase ARF6, a protein that controls intracellular trafficking, accelerates metastasis of
BRAFV600E melanoma. Prior to metastasis, our unpublished data reveal that the protein ARF6 is also required for
efficient tumor development and growth in mice with BRAFV600E melanoma. This positions ARF6 as a key
regulator at multiple points in disease progression. Indeed, our preliminary data suggest a novel role for ARF6
in MAPK signaling by regulating the nuclear localization of activated, phospho-ERK, a key effector protein for
BRAF. Thus, we hypothesize that ARF6 modulates BRAFV600E-mediated tumor progression, controlling MAPK
signaling and providing a vulnerable node for pharmacologic inhibition of both tumor growth and metastasis.
Using genetic and pharmacologic approaches, including our unique mouse models and a specific ARF6 inhibitor
that we helped develop, our goals are to dissect the roles of ARF6 in MAPK signaling, discover new role(s) for
ARF6 in tumor cell function, and test the efficacy of ARF6 inhibitors in restricting tumor progression. Pursuant to
these goals, we will: 1) Test the hypothesis that ARF6 controls MAPK signaling in BRAFV600E-melanoma; 2) Test
the hypothesis that ARF6 is critical for proliferation and survival of BRAFV600E melanoma; 3) Test the hypothesis
that pharmacologic inhibition of ARF6 has therapeutic efficacy in BRAFV600E melanoma patient-derived
xenografts (MPDX). Successful completion of the aims in this proposal will identify new mechanisms of
melanoma progression that are amenable to therapeutic intervention and may position ARF6 as a potential
therapeutic target in RAS-mutant cancers.

## Key facts

- **NIH application ID:** 10441460
- **Project number:** 5R37CA230630-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Allie H. Grossmann
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $348,844
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441460

## Citation

> US National Institutes of Health, RePORTER application 10441460, Targeting Rheostatic Mechanisms of Melanoma Progression (5R37CA230630-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10441460. Licensed CC0.

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