Abstract 6892: Ribonucleotide reductase is a potential therapeutic target in colorectal cancer

Abstract Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness and treatment response. Primary and acquired resistance limit the efficacy of available treatments, and identification of new therapeutic targets is needed to further improve patients’ outcomes. To identify actionable targets, we performed a “drop-out” loss-of-function screening with an shRNA library covering 200 drug-target genes in nine different CRC cell lines, covering the whole spectrum of molecular subtypes of CRC. Multiple screening hits were found. Among them RRM1, encoding a member of the ribonucleotide reductase complex and targeted by the FDA-approved drug clofarabine, was found to be non-dispensable in all cell lines. In vitro drug efficacy studies confirmed sensitivity to clofarabine of most CRC cell lines. In vivo testing on a CRC cell line xenograft confirmed substantial growth inhibition by clofarabine. These results unveil a possible therapeutic opportunity in colorectal cancer. Citation Format: Federica Invrea, Consalvo Petti, Claudio Isella, Enzo Medico. Ribonucleotide reductase is a potential therapeutic target in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6892.