Development of new therapeutic strategies to enhance the effectiveness of irinotecan in colorectal cancer treatment.

• DOI: 10.1200/jco.2025.43.4_suppl.217
• Publication Date: 2025-01-27T14:35:52Z
• Authors: Koji Ando; Yuho Ebata; Eiji Oki; Tomoharu Yoshizumi; Ajit Bharti

217 Background: Chemotherapy plays an important role in the treatment of colorectal cancer. Irinotecan, a topoisomerase I inhibitor, is used therapies such as FOLFIRI and FOLFOXIRI. However, many patients become resistant to irinotecan, detailed mechanisms resistance are not fully understood. The aim develop new therapeutic strategies by elucidating irinotecan resistance. Methods: We vitro approach demonstrate mechanism topoI degradation. Immunohistochemistry staining was explore biomarker for Finally, vivo strategy treatment. Results: Mechanism (topoI) degradation: investigated molecular degradation detail. After administration, double-strand breaks occur DNA, activating DNA-PK. This activated DNA-PK phosphorylates S10 residue topoI, BRCA1-BARD1 ubiquitinates phosphorylated topoI. Eventually, degraded proteasome. Colorectal cancer cell lines where occurred after administration showed Development sensitivity: created monoclonal antibody that labels (topoI-pS10). examined topoI-pS10 expression cases with history results sensitivity 87.5%, accuracy 70%, positive predictive value 70.7%, negative 87%, indicating could serve sensitivity.Development strategies: which causes resistance, carried out via ubiquitin-proteasome pathway. It expected combining proteasome blocks this pathway, will enhance irinotecan’s effectiveness. When combined inhibitor irinotecan-resistant lines, death at higher rate compared when they were combined. Similar observed experiments using mice. Conclusions: Based on degradation, we developed strategy. study suggests potential further improvements therapy.