# Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma

## TL;DR

Blocking the RAC/PAK signaling pathway improves the effectiveness of cancer drugs in treating uveal melanoma, a rare eye cancer with poor treatment options.

## Contribution

The study identifies a novel synergistic strategy combining RAC/PAK inhibition with MAPK cascade inhibitors to treat uveal melanoma.

## Key findings

- Pharmacological inhibition of RAC, PAK, and IMPDH synergizes with MAPK inhibitors to suppress uveal melanoma cell growth.
- Adding an IMPDH inhibitor to MAPK cascade inhibitors improves survival in a mouse model of uveal melanoma.
- Targeting the RAC/PAK axis offers a new approach to enhance targeted therapies for uveal melanoma.

## Abstract

Uveal melanoma is a melanocyte-derived malignancy of the eye with a high propensity for liver metastasis. Metastatic uveal melanoma is associated with high mortality and is poorly responsive to currently available therapies. Most uveal melanoma cases are driven by activating mutations in GNAQ and GNA11 genes, which convey oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway. Despite promising early results, safe doses of pharmacological inhibitors of the MAPK cascade failed to effectively control uveal melanoma in human trials. Considering the role of the RAC/PAK signaling axis as a co-regulator of the MAPK cascade, we set forth to investigate whether the efficacy of MAPK cascade inhibitors in pre-clinical models may be enhanced by direct inhibition of RAC and PAK proteins, or by indirect control of RAC via inhibition of guanylate biosynthesis. We observed that pharmacological inhibition of RAC, PAK and the key guanylate biosynthesis enzyme IMPDH significantly synergized with various inhibitors of the MAPK cascade in suppressing oncogenic signaling and the growth of uveal melanoma cells. In a mouse model, the addition of an IMPDH inhibitor to the treatment regimen significantly enhanced the ability of a MAPK cascade inhibitor to improve the survival of tumor-bearing animals. Targeting of the RAC/PAK axis provides a new strategy to increase the efficacy of targeted therapies in uveal melanoma. While RAC and PAK inhibitors are still undergoing pre-clinical development, clinically available inhibitors of IMPDH offer an opportunity to test the efficacy of this novel synergistic combination in the context of human disease.