RAC1 as a therapeutic target in colorectal cancer

OTTERSTEDT, KATIA; MALIZIA, FLORENCIA; ANSELMINO, LUICANO; MENACHO-MÁRQUEZ, MAURICIO

Congreso; XIII CAB2C, XIII SoIBio, III RiaBio - 2023; 2023

Background:Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer type worldwide. Rac1, a pivotal member of the Rho GTPases family, orchestrates cell adhesion and motility and exhibits heightened expression in tumors. Researchers are increasingly scrutinizing Rac1 as a potential therapeutic target for tumor treatment. This study aims to assess the impact of Rac1 in CRC. Given that approximately 30–40% of CRC patients harbor a KRAS mutation, we initiated an assessment of the relevance of RAC1 expression in KRAS wild-type/mutated CRCs. Initially, we accessed the TCGA-COAD dataset and stratified patients based on RAC1 expression levels using the "Survminer" package. Subsequently, we introduced an additional filter to segregate patients according to their KRAS gene status. This assessment was extended to Rac1 guanine nucleotide exchange factors (GEFs).Objective:To further elucidate the role of Rac1 in CRC, this study aimed to pinpoint genes exhibiting differential expression between patients with high and low RAC1 expression levels. The analysis was refined by segregating patients based on their KRAS gene status. By identifying these differentially expressed genes, we established a genetic signature for each patient subgroup. Subsequently, these signature genes underwent overrepresentation analysis and gene set enrichment analysis, facilitating the identification of pivotal pathways associated with each phenotype.Results:The differential genes identified in this study are strongly linked to cellular metabolism, proliferation, amyloid fiber formation, and programmed cell death. Moreover, we observed that elevated expression of RAC1 correlates with poor prognosis in patients with KRAS mutations, and several RAC1 GEFs exhibit distinct survival patterns contingent upon the presence of KRAS mutations in their genomes.Conclusions:Our comprehensive data collectively suggest that targeting Rac1 represents a promising avenue for developing novel therapies for CRC patients, particularly those harboring mutated KRAS genes.