# ARF6 function in cancers driven by RAS hyperactivation

> **NIH NIH R00** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $247,551

## Abstract

PROJECT SUMMARY/ABSTRACT
Activating mutations in RAS or mutations in RAS regulatory genes that lead to hyperactivated RAS are drivers
of human cancer. Neurofibromatosis type 1 (NF1) is a developmental disease caused by loss of the NF1 tumor
suppressor gene, which encodes neurofibromin, a large protein that inactivates RAS through its GTPase
activating function. Loss of NF1 leads to the hyperactivation of RAS and increases the risk of developing multiple
cancers, including malignant peripheral nerve sheath tumors (MPNSTs). RAS activation promotes signaling of
several downstream pathways that drive oncogenesis, including the PI3K and MAPK signaling pathways.
Although many attempts have been made to target RAS either directly or indirectly, none of them have yet been
successful in the clinic and therefore new insights into the precise mechanisms that govern RAS signaling are
needed. The small GTPase protein ARF6 has been implicated in the growth and metastasis of many cancers.
In uveal and cutaneous melanomas, ARF6 promotes the trafficking of oncogenic Gq or -catenin to appropriate
intracellular locations where signaling or transcription is enhanced. Our preliminary data suggest that ARF6 may
also be regulating RAS signaling in NF1-deficient MPNSTs by controlling RAS intracellular trafficking and that
ARF6 controls proliferation of NF1-deficient tumor cells. Activated ARF6 appears to be necessary for RAS lipid
modifications, such as palmitoylation and farnesylation, which are essential for RAS membrane localization and
for binding with its effectors, RAF and p110 (a PI3K catalytic subunit). Based on these preliminary data, we
hypothesize that ARF6 promotes tumorigenesis in NF1-deficient tissues by controlling RAS trafficking and
signaling. We will test this hypothesis by pursuing the following aims. In Aim 1, we will determine whether loss
of NF1 activates ARF6 to control tumor cell proliferation by regulating RAS subcellular localization and signaling.
These studies will involve multidisciplinary approaches to determine how NF1 regulates ARF6 and how ARF6
controls cell proliferation, RAS lipid modifications, intracellular localization, and signaling. In Aim 2, we will assess
ARF6 function in tumor growth in an orthotopic xenograft mouse model of NF1-deficient human MPNST. These
studies will allow us to determine how ARF6 knockdown or pharmacologic inhibition affects in vivo growth of
tumors derived from human cancer cells in an immunocompromised mouse model. In Aim 3, we will determine
whether ARF6 is necessary for tumor formation and growth in a genetically engineered mouse model of NF1-
deficient cancers. These studies will involve either knocking out Arf6 or pharmacologically inhibiting ARF6 in
immunocompetent Nf1+/-; Trp53+/- mice to determine the in vivo role of ARF6 in NF1-deficient tumorigenesis in
the presence of a competent immune system. This proposal will provide essential training in multidisciplinary
approaches and expand the candida...

## Key facts

- **NIH application ID:** 10473804
- **Project number:** 5R00CA230312-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Jae Hyuk Yoo
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $247,551
- **Award type:** 5
- **Project period:** 2018-07-03 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473804

## Citation

> US National Institutes of Health, RePORTER application 10473804, ARF6 function in cancers driven by RAS hyperactivation (5R00CA230312-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10473804. Licensed CC0.

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