Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex

• Published in: Nature communications 2023-06, Vol.14 (1), p.3762-20, Article 3762
• Main Authors: Sun, Yilun, Baechler, Simone A., Zhang, Xiaohu, Kumar, Suresh, Factor, Valentina M., Arakawa, Yasuhiro, Chau, Cindy H., Okamoto, Kanako, Parikh, Anup, Walker, Bob, Su, Yijun P., Chen, Jiji, Ting, Tabitha, Huang, Shar-yin N., Beck, Erin, Itkin, Zina, McKnight, Crystal, Xie, Changqing, Roper, Nitin, Nijhawan, Deepak, Figg, William Douglas, Meltzer, Paul S., Yang, James C., Thomas, Craig J., Pommier, Yves
• Format: Article
• Language: English
• Subjects: 631/337/1427/1979; 631/337/458/2288; 692/4028/67/1059; Cancer; Cancer therapies; Cell cycle; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Crosslinking; Cullin; Cytotoxicity; Degradation; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA topoisomerase; Enzyme inhibitors; Enzymes; Genetic screening; Humanities and Social Sciences; Humans; Irinotecan; Ligases - metabolism; Metabolites; Metastasis; multidisciplinary; Organoids; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Replication; RNA-Binding Proteins; Science; Science (multidisciplinary); Topoisomerase I Inhibitors - pharmacology; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39374-9

Colorectal cancers (CRCs) are prevalent worldwide, yet current treatments remain inadequate. Using chemical genetic screens, we identify that co-inhibition of topoisomerase I (TOP1) and NEDD8 is synergistically cytotoxic in human CRC cells. Combination of the TOP1 inhibitor irinotecan or its bioactive metabolite SN38 with the NEDD8-activating enzyme inhibitor pevonedistat exhibits synergy in CRC patient-derived organoids and xenografts. Mechanistically, we show that pevonedistat blocks the ubiquitin/proteasome-dependent repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) induced by TOP1 inhibitors and that the CUL4-RBX1 complex (CRL4) is a prominent ubiquitin ligase acting on TOP1-DPCs for proteasomal degradation upon auto-NEDD8 modification during replication. We identify DCAF13, a D DB1 and C ullin A ssociated F actor, as the receptor of TOP1-DPCs for CRL4. Our study not only uncovers a replication-coupled ubiquitin-proteasome pathway for the repair of TOP1-DPCs but also provides molecular and translational rationale for combining TOP1 inhibitors and pevonedistat for CRC and other types of cancers. Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer therapy. Here, the authors identify pevonedistat, NEDD8 inhibitor, as synergistic with irinotecan by blocking neddylation-activated ubiquitin/proteasomal degradation of TOP1-DPC.