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Abstract Resistance to cancer treatment remains a significant obstacle in curing patients with cancer. Despite recent advancements in novel drug targets for cancer therapeutics, patients often develop treatment resistance even after initial disease remission, leading to tumor relapse. To investigate the mechanisms responsible for developing resistance to standard-of-care therapies, it is essential to gain insights into the stepwise progression leading to complete resistance. Recent research has revealed that cancer cells can evade the effects of chemotherapy and targeted therapy by entering a reversible and slow proliferation state known as the drug-tolerant persister (DTP) state. This DTP state allows cancer cells to survive drug therapy long enough for additional mechanisms of acquired drug resistance to develop. HUB Organoids® or patient-derived organoid (PDO) models are derived from patient tissues, making them more physiologically relevant than traditional cell lines. Thus, studying drug persistence and resistance in PDO models is more likely to reflect in vivo conditions. This study demonstrates the successful development of persistent and resistant CRC PDO models to standard-of-care therapies. All models were characterized using whole exome sequencing and RNA sequencing to confirm their persistent or resistant state and to identify possible pathways involved in developing therapy resistance, as well as potential new drug targets. In conclusion, developing persistent and resistant PDO models is crucial for understanding drug resistance mechanisms, enabling the development of more effective and personalized cancer treatments, and advancing our overall knowledge of how resistance develops in cancer patients. Citation Format: Yasmine Abouleila, Mayke Doorn, Roel Verkerk, Joris Maas, Carla Verissimo, Sylvia Boj. Resistant PDO models: Unraveling drug resistance mechanisms for discovering new drug targets abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 535.
Abouleila et al. (Fri,) studied this question.