A COMPREHENSIVE APPROACH TO IDENTIFYING THERAPEUTIC OPPORTUNITIES IN 5-FU-RESISTANT COLORECTAL CANCER: RAC1 PATHWAY AS A POTENTIAL TARGET

LUCIANO ANSELMINO; FLORENCIA MALIZIA; AYLEN AVILA; NAHUEL CESATTI LALUCE; MACARENA MAMBERTO; LUCIA ZANOTTI; CECILIA FARRÉ; MAURICIO MENACHO MÁRQUEZ

Congreso; REUNIÓN CONJUNTA SAIC SAFIS ALACF 2024; 2024

Colorectal cancer (CRC) is the third most common cancer globally and a leading cause of death. 5-fluorouracil (5-FU) is a widely used chemotherapy for CRC, either alone or in combination, but resistance occurs in about 50% of cases. To understand the mechanisms behind CRC resistance or recurrence after 5-FU treatment, we conducted a comprehensive study using in silico, in vitro, and in vivo approaches. We identified differentially expressed genes between recurrent and non-recurrent phenotypes after 5-FU monotherapy across public gene expression datasets (FDR≤0.05, |logFC|>1). These DEGs were used for pathway enrichment (p-value≤0.05), gene set analysis (FDR-P ≤ 0.05, |NES|>2), and transcription factor motif detection (FDR-P3). Additionally, we created a merged gene expression matrix from patients treated with FOLFLOX and FOLFIRI regimens, applying feature selection and machine learning techniques to identify recurrence predictor genes. Our findings suggested Rac1 pathway as a potential target to overcome 5-FU resistance. Pull-down experiments confirmed significantly increased Rac1 activity in 5-FU-resistant CRC cells compared to sensitive ones. Guided by our bioinformatics analysis, we used drug repositioning databases to identify drugs that could restore 5-FU sensitivity (p