Abstract B050: Identification of novel molecular vulnerabilities in colorectal cancer through integrated transcriptomic profiling and functional genomics

Abstract Colorectal cancer (CRC) remains a major global health burden, contributing significantly to morbidity and mortality worldwide. Despite advances in understanding the molecular landscape of CRC and the development of targeted therapies, there is still a critical need for novel treatment strategies that address specific molecular vulnerabilities in CRC. To address this challenge, we developed a robust and scalable platform for target discovery, centered on identifying synthetic lethal (SL) interactions linked to key oncogenic drivers such as APC, KRAS, and SMAD4. Using colorectal cancer (CRC) as a model, we integrated genomic and transcriptomic analyses across a diverse set of biologically relevant systems, including human intestinal stem cell (hISC)-derived isogenic cancer models that accurately replicate tumor genotypes, patient-derived cells (PDCs), and clinical tumor specimens. At the heart of our platform is CRISPR-based functional screening, enabling systematic interrogation of gene dependencies. To benchmark our engineered models, we applied machine learning to RNA sequencing data, comparing them against a large cohort of clinically annotated CRC transcriptomes. This approach enabled precise molecular subtyping, detailed characterization of gene expression programs, and the identification of novel, tractable vulnerabilities specific to genetically defined subgroups. Candidate targets were prioritized based on therapeutic relevance and selective efficacy in cancer cells, while sparing untransformed hISCs. Our findings not only advance early-stage target identification and validation but also support the initiation of precision drug discovery programs focused on CRC subtypes driven by APC, KRAS, and SMAD4 mutations. Moreover, the versatility of our platform enables its application to other malignancies. In summary, we present an integrated, high-resolution framework for uncovering novel molecular dependencies in CRC, providing a foundation for precision oncology and future therapeutic innovation. Citation Format: Eliza Zimoląg, Joanna Szuszkiewicz, Marcin Serocki, Marcin Duleba, Oleksii Bryzghalov, Izabella Więckowska, Marcelina Chmiel, Barbara Lipert, Katarzyna Sarad, Julia Wirkijowska, Szymon Worszyło, Dariusz Klonski, Michał Mikula, Rafał Dziadziuszko, Andrew Thomason, Krzysztof Brzózka, Andrzej Mazan. Identification of novel molecular vulnerabilities in colorectal cancer through integrated transcriptomic profiling and functional genomics [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B050.