Abstract 4710: Heterogeneous efficacy patterns of KRAS inhibitors in digestive cancers

Abstract Introduction: KRAS is a well-studied oncogenic driver in a variety of solid tumors, playing a pivotal role in cell proliferation and survival. Its involvement in digestive cancers, including colorectal cancer (CRC) has made it an attractive target for therapeutic development. However, efforts to expand KRAS-targeted assets in these cancers are hindered by the complex and heterogeneous expression patterns of KRAS in solid tumors, which complicate effective targeting and the translation of therapeutic efficacy across patient populations. Furthermore, clinical studies have shown that resistance mechanisms compensate KRAS inhibition and require the development of efficient combination therapies. Methods: To address these challenges, we collected 24 patient-derived organoids (PDO) representing the molecular diversity of KRAS-driven CRC and PDAC with 5 KRAS G12C variants, 8 KRAS G12D variants and 6 KRAS G12R variants. In-depth molecular and transcriptomic characterization was performed with a particular focus on co-mutation patterns for each KRAS variant. Then the PDOs were screened against a KRAS drugs with and without combination with an EGFR inhibitor. The efficacy of the drugs were systematically compared among different variant populations. Results: Our findings demonstrate that the PDO models faithfully recapitulate the KRAS heterogeneity observed in primary tumors, providing a robust preclinical platform for testing KRAS-targeted therapies. Strong synergistic effects were identified when using KRAS and EGFR inhibitors simultaneously, matching prior clinical trial results. This model system allows us to dissect the impact of KRAS expression patterns on therapeutic response and resistance mechanisms. Conclusion: Our study emphasizes the utility of PDOs as a precision tool for advancing KRAS-targeted strategies in complex solid tumors and highlights the potential for individualized approaches in the treatment of KRAS-driven digestive cancers. Citation Format: Gustave Ronteix, Jérôme Caron, Rafal Pietrzak, Gizem Altay, Fabiana Graziosi, Lélia Polit, Anna-Rose Gryspeert, Jacques RR Mathieu, Jérôme Cartry, Sabrina Bedja, Alice Boilève, Michel Ducreux, Sophie Postel-Vinay, Fanny Jaulin. Heterogeneous efficacy patterns of KRAS inhibitors in digestive cancers [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 4710.