Abstract 2973: Discovery of novel synthetic lethal targets for effective and safe colorectal cancer therapies

Colorectal cancer (CRC) poses a significant global health burden, highlighting the urgent need for innovative and effective treatment options. This study focuses on the discovery and validation of novel therapeutic targets, particularly synthetic lethal (SL) interactions, to exploit specific genetic vulnerabilities in CRC cells and enable the development of safer and more effective therapies. We employed a comprehensive strategy integrating healthy cells, genetically engineered isogenic cancer models derived from human intestinal stem cells (hISCs) with patient-derived xenografts (PDXs) and primary cell cultures. Using CRISPR/Cas9 technology, we introduced key CRC-associated mutations into the hISCs to replicate disease-specific contexts. Transcriptome profiling, coupled with machine learning, validated these models as robust, clinically relevant representations of tumor biology by aligning them with clinical datasets. Genome-wide CRISPR/Cas9 screenings conducted across the isogenic and patient-derived models revealed actionable vulnerabilities, including the identification of genes that are synthetically lethal with APC and KRAS mutations. Discovered SL targets were rigorously validated in vitro and in vivo using patient-derived cells with matching mutational profiles. This integrative approach bridges preclinical and clinical research, ensuring translational relevance. By identifying and validating SL targets tailored to CRC mutational landscapes, we provide a robust foundation for the development of novel treatment options for CRC patients. Citation Format: Andrzej Mazan, Marcin Duleba, Eliza Zimolag, Joanna Szuszkiewicz, Marcin Serocki, Joanna Krawczyk, Oleksii Bryzghalov, Agata Stachowicz-Walaszek, Izabella Wieckowska, Marcelina Chmiel, Alexander Kurzejamski, Barbara Lipert, Katarzyna Sarad, Michal Mikula, Rafal Dziadziuszko, Tomasz Rzymski, Andrew Thomason, Krzysztof Brzozka. Discovery of novel synthetic lethal targets for effective and safe colorectal cancer therapies [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 2973.