Abstract 5706: A patient-derived organoid screening platform as a powerful tool to study efficacy of KRAS inhibitors

Abstract Kirsten rat sarcoma (KRAS) gene is a proto-oncogene frequently mutated in various cancer types. Upon activation by growth factors such as Epidermal Growth Factor (EGF), KRAS initiates signaling pathways promoting cell proliferation and survival. Activation KRAS mutations are most common in colorectal cancer (CRC), Pancreatic Ductal Adeno Carcinoma (PDAC) and Non-Small Cell Lung Cancer (NSCLC) and are associated with worse disease outcomes. Though KRAS is an interesting target for cancer treatment, the development of specific KRAS inhibitors has, for many years, been challenging due to its small and smooth binding pocket, making KRAS a challenging “druggable” protein. Recently, advances have been made in this area, with the development and approval for clinical use of the KRASG12C inhibitors (Sotorasib and Adagrasib). These developments can pave the way for the design of novel compounds targeting KRAS G12C and other KRAS mutations, which can be accelerated when developed in patient-relevant preclinical models. Patient-derived organoids (PDOs) or HUB Organoids® are generated from the adult stem cells of normal and malignant tissues of epithelial organs, including the colon, pancreas, and lung. HUB Organoids recapitulate tissue physiology, molecular heterogeneity, and morphological and functional characteristics, including mimicking patient response. Organoids are suitable for high-throughput screening and serve as a platform for testing drug efficacy and safety. In this study, we showcase the suitability of our PDO-based platform for screening the efficacy of several KRAS inhibitors in 4 weeks. Eight KRAS inhibitors in different clinical research stages were tested in a panel of over 20 PDOs (including CRC, PDAC and NSCLC) harboring different KRAS mutations (G12C, G12D, Q61R, G13C, G12V and G12S) and using an ATP-based cell viability readout. As expected, various responses were identified among the 20 PDOs. In addition, the results show specific responses of G12C and G12D mutants to KRASG12C and KRASG12D-selective inhibitors, respectively. KRASG12CPDO resistance to KRASG12C inhibitors was alleviated by combinatorial treatment with an EGFR inhibitor, which aligns with the KRASi resistance mechanism driven by EGF signaling. In conclusion, our PDO platform effectively captures the efficacy and specificity of KRAS inhibitors in models with different KRAS mutations. The HUB PDO platform is valuable for studying combinatorial treatments to overcome KRAS inhibitor resistance, highlighting the potential of PDOs in developing novel KRAS inhibitors. Citation Format: Merel Derksen, Mariana Silva, Gerben ten Hag, Nilofar Ehsani, Yasmine Abouleila, Vineeta Adegbenro, Annemarie Buijs, Mayke Doorn, Nikki van Dorp, Javier Frias Aldeguer, Foteini Gkogkou, Yara Hendriksen, Ricardo Korporaal, Ka Wai La, Joris Maas, Francisco Morales-Rodrigues, Daniele Mori, Sumeyra Mucuk, Cesar Oyarce, Nima Salehi, Anna Schepers, Marvin Statia, Roel Verkerk, Timo Voskuilen, Rene Overmeer, Farzin Pourfarzad, Sylvia F. Boj. A patient-derived organoid screening platform as a powerful tool to study efficacy of KRAS inhibitors [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 5706.