# The role of RAC1 in resistance to targeted therapies in cancer

## TL;DR

RAC1, a protein involved in cell growth, contributes to cancer drug resistance when mutated, and new strategies are being explored to target it.

## Contribution

The paper highlights RAC1's role in drug resistance and outlines potential therapeutic strategies to address RAC1-related challenges in cancer treatment.

## Key findings

- RAC1 mutations combined with BRAF, NRAS, or NF1 mutations lead to drug resistance and poor patient outcomes.
- RAC1 is difficult to target due to its essential cellular functions, but strategies targeting its activators and localization are being explored.
- Regulating RAC1 through epigenetic or direct targeting may offer future therapeutic options.

## Abstract

RAC1 is a small 21 kDa RHO GTPase that plays a pivotal role in regulating actin cytoskeletal dynamics and cell growth. Alterations in the activity of RAC1 are implicated in a range of diseases, including cancer. Increased RAC1 activity, due to overexpression and/or activating mutations, drives transcriptional upregulation, reactive oxygen species production, mesenchymal-to-epithelial transition, membrane ruffling, and uncontrolled cell proliferation, which are hallmarks of an oncogenic phenotype. While RAC1-activating mutations alone do not appear sufficient to transform cells, their combination with other common mutations, such as BRAF, NRAS, or NF1, have been linked to drug resistance and significantly worsen patient prognosis and hinder treatment responses. The precise mechanisms underlying drug resistance, and the regulation of RAC1 splicing remain poorly understood. RAC1 is a challenging therapeutic target due to its ubiquitous presence and essential cellular functions. To date, there are no established standard treatments for cancers that harbour an additional RAC1 mutation or for RAC1-mediated drug resistance. Current experimental strategies aim to target RAC1 localization, its activators (e.g. guanine nucleotide exchange factors) and downstream effectors. Regulating RAC1 expression by targeting epigenetic regulators, and direct targeting of RAC1 itself, may also be possible in the near future.