Abstract 5551: From persistence to resistance: insights into the mechanisms of drug tolerance in cancer therapy using patient-derived organoids

Abstract Resistance to cancer treatment remains a significant obstacle in curing cancer patients. Despite recent advancements in novel cancer drugs, patients often experience treatment resistance even after initially responding to therapy, leading to tumor relapse. To understand how resistance develops against standard cancer therapies, it is essential to study the gradual changes leading to full resistance. Recent research shows that cancer cells can evade the effects of chemotherapy and targeted therapies by entering a reversible, slow-growing phase called the drug-tolerant persister (DTP) state. In this DTP state, cancer cells survive drug treatment long enough to begin accumulating mutations and eventually develop additional mechanisms of irreversible resistance. Patient-derived organoid (PDO) models, also known as HUB Organoids®, are directly derived from patient tissues, making them more physiologically relevant than traditional cell lines. This study highlights the value of PDO models in studying drug persistence and resistance, as they are more likely to reflect in-vivo conditions. Here, we demonstrate the successful development of colorectal cancer (CRC) PDO models that can persist and resist standard therapies. These models were characterized using whole exome sequencing and bulk RNA sequencing to assess their persistent or resistant state and to identify potential pathways and new drug targets involved in resistance. In conclusion, developing persistent and resistant PDO models is essential for understanding the mechanisms behind drug resistance. This research contributes to developing patient-relevant preclinical models to develop more effective and personalized cancer treatments and expands our overall understanding of how resistance develops in cancer patients. Citation Format: Yasmine Abouleila, Timo Voskuilen, Mayke Doorn, Roel Verkerk, Joris Maas, Carla Verissimo, Sylvia F. Boj. From persistence to resistance: insights into the mechanisms of drug tolerance in cancer therapy using patient-derived organoids [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 5551.