Abstract 2989: ONCO Prime platform enables discovery of synthetic lethal targets for genetically stratified cancers

Abstract Colorectal cancer (CRC) remains a leading cause of cancer mortality, underscoring the need for new, mechanism-based therapeutic strategies. Using the ONCO Prime discovery and validation platform, based on genome wide CRISPR/Cas9 screenings across clinically relevant models, we identified novel treatment options for genetically stratified CRC patients The ONCO Prime platform integrates healthy human intestinal stem cells (hISCs), isogenic CRC models carrying key driver mutations (APC, KRAS), and patient-derived primary cultures. All types of models can be genetically manipulated or used in the high-throughput setting for the drug testing. Transcriptomic and machine learning analyses confirmed that these models faithfully recapitulate CRC molecular diversity and clinical behavior. Systematic CRISPR/Cas9 loss-of-function screenings revealed multiple synthetic lethal (SL) interactions, uncovering target genes with first-in-class therapeutic potential. Additionally, using a clinical grade drug that is FDA-approved in other indications, we achieved proof of concept in genetically stratified CRC models, demonstrating strong efficacy as monotherapy in vitro. These data validate ONCO Prime’s translational capability to uncover clinically actionable vulnerabilities and deliver tangible therapeutic candidates. This work provides a robust foundation for drug discovery programs and strategic partnerships built on ONCO Prime’s ability to bridge functional genomics with therapeutic development. Our first proof of concept establishes ONCO Prime as a scalable platform to drive the next generation of precision, first-in-class oncology therapies. Citation Format: Andrzej Mazan, Eliza Zimolag, Joanna Szuszkiewicz, Marcin Serocki, Oleksii Bryzghalov, Izabella Wieckowska, Marcelina Chmiel, Katarzyna Sarad, Julia Wirkijowska, Wiktoria Luczak, Szymon Woroszylo, Dariusz Klonski, Kamil Kus, Andrew Thomason, Michal Mikula, Rafal Dziadziuszko, Krzysztof Brzozka. ONCO Prime platform enables discovery of synthetic lethal targets for genetically stratified cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2989.