Proteasome inhibitor, ixazomib prevents topoisomerase‐I degradation and reverses irinotecan resistance in colorectal cancer
values compared with SN-38 alone. Mechanistically, ixazomib prevented proteasome-mediated degradation of ubiquitinated topoI, restoring its stability. In vivo, the combination significantly suppressed tumor growth in a DLD-1 xenograft model compared with SN-38 alone. These findings indicate that UPP-dependent topoI degradation is a key mechanism underlying irinotecan resistance in colorectal cancer. Pharmacological inhibition of the proteasome effectively prevents topoI loss and restores irinotecan sensitivity, suggesting that proteasome inhibitors such as ixazomib may serve as promising therapeutic partners for camptothecin-based chemotherapy.
Authors
- Ajit Bharti (ORCID: https://orcid.org/0000-0001-7972-6688)
- Allison Berger (ORCID: https://orcid.org/0000-0003-1217-2005)
- Elizabeth C. Unan (ORCID: https://orcid.org/0000-0002-7742-9214)
- Koji Ando (ORCID: https://orcid.org/0000-0002-0149-1505)
- Hirofumi Hasuda
- Yuho Ebata (ORCID: https://orcid.org/0000-0002-5636-3236)
- Siddhartha Pulukuri (ORCID: https://orcid.org/0000-0002-4393-5813)
- Eiji Oki
- Koshi Mimori
- Aahana Tiku
- Tomoharu Yoshizumi
Institutions
- Boston University (US)
- Kyushu University (JP)
- National Kyushu Medical Center (JP)
- Kyushu University Hospital (JP)
- Takeda (United States) (US)
- BioScience Laboratories (United States) (US)
- Kyushu University Beppu Hospital (JP)
Publication Details
- Journal
- Molecular Oncology
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1002/1878-0261.70256
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00