Abstract 1824: Harnessing a radiation-resistant organoid platform to propose novel strategies for precision treatment of advanced oral cancer

Abstract Oral squamous cell carcinoma (OSCC) has high recurrence rates and limited treatment options, with 40-60% of patients diagnosed at advanced stages (III/IV). Despite surgery following radiotherapy, over 40% of patients with advanced OSCC experience recurrence, with 70% being locoregional. Postoperative radiotherapy reduces recurrence but causes significant side effects, such as xerostomia and osteoradionecrosis. The challenge of accurately reflecting the clinical characteristics and tumor heterogeneity of oral cancer hinders clinical application. Therefore, research models that preserve patient traits are essential for developing tailored treatments, reducing side effects, and improving outcomes. In this study, we used a radiotherapy-relapse mimicking patient-derived organoid model to identify intrinsic radiation resistance and overcome it in advanced oral cancer. Radiation-resistant (RR) organoids were successfully developed by gradually increasing radiation intensity over 10 passages, with a total dose of 60 Gy. Of the 23 cases, 14 successfully generated RR organoids. These RR organoids exhibited enhanced radiation resistance and proliferation. Evaluation with multiple radiation fractions proved more reliable than single-fraction assessments, as it minimized interference from proliferation-related factors. By linking patient recurrence status with the establishment of RR organoids, it was observed that organoids derived from recurrent patients had a higher success rate. This suggests that radiation resistance is driven by pre-existing subclones. The characteristics of subclones that survived radiation exposure were examined through differential gene expression (DEG) analysis, revealing upregulation of genes related to the cell cycle, DNA damage repair, and inflammatory response pathways, while genes associated with apoptosis and differentiation were downregulated. Inhibitors targeting the altered pathways were selected, and combination treatments with radiation were performed. The ATR inhibitor, BAY1895344, demonstrated synergistic effects. Finally, genes with sequentially altered mRNA levels based on radiation responsiveness were selected to develop the radiation resistant index (RRI). This study aims to address the limitations of existing preclinical models by utilizing patient-derived organoids that preserve tumor heterogeneity, thereby providing a platform and treatment prediction for clinically relevant research. These findings are anticipated to contribute significantly to the development of precision medicine-based therapeutic strategies for advanced oral cancer. Citation Format: Sumin Kang, Mi Rim Lee, Jonghyun Lee, Dongkwan Shin, Sun-Young Kong, Jong-Ho Lee, Ikjae Kwon, Dohyun Kwon, Soung-Min Kim, Joo Yong Park, Wonyoung Choi, Jiyoung Lee, Yu-Sun Lee, Hye Won Shon, Gyeongmin Kang, Sung Weon Choi, Yun-Hee Kim. Harnessing a radiation-resistant organoid platform to propose novel strategies for precision treatment of advanced oral cancer [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 1824.