The role of RAC1 in resistance to targeted therapies in cancer

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.

Keywords: RAC1; RHO GTPases; Signal transduction; cancer; drug resistance.

Figure 1.

RAC1 mutations and their association with diverse diseases. A) RAC1, localized on chromosome 7 (7p22.1), encodes a 192 amino acid 21 kDa protein. The RAC1 promoter is localized 113–30 bp upstream the transcription initiation site. RAC1 has 7 exons that can produce two proteins: RAC1 (exons 1–6) and the fast-cycling isoform RAC1B (exons 1–3, 3b, 4–6). Exon 3b adds a 19 amino acid in-frame insertion after the switch-II domain (orange) that induces an open switch I conformation and a highly mobile switch II. RAC1s tertiary structure consists of a 6 strand β-sheet domain surrounded by six α helices. RAC1 (PDB-3TH5) [9], and RAC1B (PDB-1RYF) [10] protein models were generated using swissmodel.Expasy.org B) RAC1 is tightly regulated: decreased RAC1 signalling is related to neurodegenerative disorders, mental retardation and micro- and macrocephaly, epilepsy and cardiovascular diseases; while increased activity of RAC1 can accelerate cells oncogenic phenotype, confer drug resistance tumours and worsen patients prognosis. Created in BioRender. Uribe, C. (2025) https://bioRender.com/e76i718

Figure 2.

Targeting RAC1 regulation and downstream effectors. RAC1’s GDP-to-GTP exchange is stimulated by guanine-nucleotide exchange factors (GEFs) and inhibited by GTPase activating proteins (GAPs) which accelerate the intrinsic hydrolysis of GTP to GDP; or by GDP-dissociation inhibitors (GDIs) that sequester RAC1 in the cytoplasm. Drugs against RAC1 target its localization, its guanine nucleotide effectors (GEFs), interact directly with RAC1 or RAC1-GTP, or target RAC1 downstream effectors. Created in BioRender. Uribe, C. (2025) https://BioRender.com/e76i718.