# Targeting the Rac1 signaling pathway in malignant melanoma

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2021 · $427,763

## Abstract

PROJECT SUMMARY/ABSTRACT
Recent advances in sequencing technology have helped uncover a variety of new driver mutations in malignant
melanoma, including recent discoveries of activating mutations in the genes encoding the guanine-nucleotide
exchange factor PREX2 and its small GTPase substrate, RAC1. Activating mutations in RAC1 are of special
interest, as tumors bearing this mutation are refractory towards current targeted therapeutic agents.
The presence of activating PREX2 and RAC1 mutations in a significant fraction of human melanoma suggest
that such tumors could be vulnerable to small molecule inhibitors that target its key kinase effectors, such as
Group A p21-activated kinases (PAK1, -2, and -3), and phosphatidylinositol-3 kinases, in particular PI3Kβ. In
preliminary studies, we have established that Group A PAKs are critical for oncogenic signaling by RAC1 in a
zebrafish model and in RAC1-mutant human melanoma cells. These effects form the basis for Specific Aim 1,
in which we use a new method for signaling analysis to establish the activity of the entire kinome in RAC1, BRAF,
and NRAS-mutant melanocytes. In Aim 2, we will then test specific PAK and PI3K small molecule inhibitors for
their ability to block the effects growth and survival effects of RAC1, as well as determine likely pathways of drug
resistance by determining the activity of the kinome before and after drug treatment. In the third aim, we will
evaluate a new genetically-engineered mouse model of RAC1-mutant melanoma for use in preclinical studies.
Such a model will provide a clinically relevant system to study RAC1 signaling in melanoblast development as
well as a rapid testing platform to evaluate therapeutic agents in melanoma.

## Key facts

- **NIH application ID:** 10246313
- **Project number:** 5R01CA227184-04
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** JONATHAN CHERNOFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,763
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246313

## Citation

> US National Institutes of Health, RePORTER application 10246313, Targeting the Rac1 signaling pathway in malignant melanoma (5R01CA227184-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246313. Licensed CC0.

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