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

作者：Yilun Sun, Simone Andrea Baechler, Xiaohu Zhang, Suresh Kumar, Valentina M. Factor, Yasuhiro Arakawa, Cindy H. Chau, Kanako Okamoto, Anup Y. Parikh, Robert L. Walker, Yijun P. Su, Jiji Chen, Tabitha C. Ting, Shar-Yin Naomi Huang, Erin Beck, Zina Itkin, Crystal G. McKnight, Changqing Xie, Nitin Roper, Deepak Nijhawan, William Douglas Figg, Paul S. Meltzer, James Chih-Hsin Yang, Craig J. Thomas, Yves G. Pommier · 发表于：Nature Communications · 年份：2023 · DOI：10.1038/s41467-023-39374-9 · 被引用次数：29 · 研究领域：Cancer therapeutics and mechanisms、Lung Cancer Research Studies、DNA Repair Mechanisms

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 DDB1 and Cullin Associated Factor, 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.