Abstract 6845: Evaluation of individual drug response to tyrosine kinase inhibitor treatment in precision-cut tumor slices of gastrointestinal stroma tumors

Abstract Gastrointestinal stromal tumors (GIST) are the most prevalent mesenchymal tumor entity of the gastrointestinal tract and serve as a key example for targeted therapies with tyrosine kinase inhibitors (TKI) such as imatinib, in tumors with the most frequent mutations in PDGFRA or c-Kit. Although TKIs have significantly improved the overall survival rates of GIST patients, there are currently no treatment options for imatinib-resistant tumors and tumors without identifiable driver mutations. So far, current sarcoma research mostly relies on expensive mouse models or 2D cell culture that do not integrate the tumor microenvironment (TME). Therefore, clinically relevant, patient-derived 3D GIST models that include cells of the TME are urgently needed. In this study, we tested the feasibility of precision-cut tumor slices (PCTS) as a preclinical model for personalized GIST research. PCTS are patient-derived 3D tissue slices that enable the study of interactions between tumor cells and cells of the surrounding TME. For this, primary GIST tumors were cut into 250µm thick slices and cultured for up to two weeks with or without standard TKI treatment. Tumor morphology and cell composition was analyzed via immunohistochemical (IHC) and multiplex immunofluorescence (mIF) staining, which enabled the simultaneous detection of up to six different markers on one FFPE tissue section. The downstream analysis included a machine-learning based workflow that allowed the comparison of biomarker expression and spatial immune cell distribution in the PCTS stromal and tumor areas before and after treatment. Comparison between primary tumor and PCTS revealed a preserved tumor morphology and heterogeneous cell composition throughout culture. In addition, serum levels of various cytokines were assessed with LEGENDPlex assays and correlated with the PCTS cell composition. The in vitro response of PCTS to TKI-based therapies was analyzed via IHC staining and ATP-based viability assays. PCTS from tumors with PDGFRA mutations were expected to be imatinib-resistant, while PCTS from tumors with c-KIT mutations were considered imatinib-sensitive. Sequencing analyses determined the PDGFRA or c-KIT mutational status showing that all patients harbored either a PDGFRA or a c-KIT mutation. PCTS treatment response was compared to the mutational status and if available to clinical follow-up data. Of all PCTS that responded to imatinib therapy, two cases matched the anticipated clinical outcome. PCTS provide a clinically relevant new model system for GIST to explore the development of therapy response to TKI-based treatment and to investigate novel GIST treatments such as immunotherapies and combination treatments. The work is supported by the Robert Bosch Stiftung, Stuttgart, Germany Citation Format: Dina Mönch, Julia Thiel, Meng Dong, Annika Maaß, Annette M. Staiger, Katrin Kurz, German Ott, Philipp Renner, Tobias Leibold, Thomas Mürdter, Matthias Schwab, Marc-Hendrik Dahlke, Jana Koch. Evaluation of individual drug response to tyrosine kinase inhibitor treatment in precision-cut tumor slices of gastrointestinal stroma tumors [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 6845.