# Efficacy of combined inhibition of BRAF, MEK, and FAK in melanoma patient derived xenografts

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $125,000

## Abstract

Summary
“This application is being submitted in response to the Notice of Special Interest (NOSI) identified as
NOT-CA-21-009.” Significant advances in melanoma research have resulted in new therapies that have
remarkably improved the management and overall survival of melanoma. However, many patients still succumb
to the disease and more than half of all melanoma deaths are due to brain metastases. As a means to overcome
this challenge, we developed a novel mouse model that allows postnatal delivery of genes of interest to
melanocytes. Using genomic and proteomic data from human melanoma samples, we tested several gene
combinations for their ability to induce metastatic melanoma in vivo. Hyperactivation of the PI3K/AKT pathway
in the context of mutant BRAF and CDKN2A loss resulted in the development of spontaneous melanoma with
full penetrance and a mean survival of only 6 weeks. The majority of these mice also developed multiple
metastases to the lungs and brain. This model mimics the human disease genetically, histologically, and by sites
of metastasis. Importantly, this model system provides a powerful platform to further study the mechanisms of
melanoma metastasis. Elucidation of this network will allow the identification of key pathway nodes that
represent potential therapeutic targets to disrupt this process. We used next generation sequencing and
proteomics analysis of non-metastatic and metastatic tumor samples to identify downstream targets of AKT1
implicated in melanoma brain metastasis. Our data showed that tumors expressing activated AKT1 displayed
elevated levels of focal adhesion (FA) factors and phosphorylated focal adhesion kinase (P-FAK). In addition,
mutant AKT1 expression increased invasion and this was reduced by pharmacological inhibition of either AKT
or FAK. Moreover, loss of PTEN, which also results in increased FAK activity, cooperated with activated AKT1
to further enhance brain metastasis in vivo. Despite these promising preliminary findings, a critical gap still
remains in determining whether the AKT1-FAK-PTEN axis can be exploited as a therapeutic target in this
disease. Our long-term goal is to use this knowledge to develop novel melanoma therapies and improve patient
outcomes. Pursuant to this goal, we have formed a collaboration with Drs. Menhard Herlyn and Michael Davies,
Principal Investigators of the U54-funded melanoma PDX program. This collaboration will bring together the
melanoma PDX expertise of Drs. Herlyn and Davies with the AKT-FAK-PTEN signaling expertise of Dr. Holmen.
Together, we will test the hypothesis that combined inhibition of BRAF, MEK, and FAK will inhibit the growth of
primary melanoma as well as established brain metastases. Successful completion of the aims in this proposal
will significantly impact the field by laying the groundwork for translation into clinical trials, leading to new and
better treatments for patients with brain metastases and those who are at high risk of developing bra...

## Key facts

- **NIH application ID:** 10326693
- **Project number:** 3R01CA121118-11A1S1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Sheri L Holmen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $125,000
- **Award type:** 3
- **Project period:** 2007-04-13 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326693

## Citation

> US National Institutes of Health, RePORTER application 10326693, Efficacy of combined inhibition of BRAF, MEK, and FAK in melanoma patient derived xenografts (3R01CA121118-11A1S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326693. Licensed CC0.

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