Abstract:
Recently, we have discovered the small-molecule degraders of ubiquitin-like modifier 1 (SUMO1) that has been considered as undruggable oncoprotein. The degrader compounds degrade SUMO1 oncoprotein through activation of Cullin-1 E3 ligase-mediated ubiquitination of the protein in colon cancer cells and suppress the growth of patient derived xenografts (PDXs) of advanced colon cancer. Advanced colon cancer is resistant to the standard chemotherapy regimen FOLFOX (5-fluorouracil, oxaliplatin, leucovorin). Here, we report the synergy of the combination of SUMO1 degraders and FOLFOX in treatment of advanced colon cancer. In a CRISPR-Cas9 genome wild knockout screen, we found that glucose-6-phosphate dehydrogenase (G6PD) is involved in the activity of SUMO1 degraders. In analysis of the Cancer Genome Atlas (TCGA) database, we found that G6PD gene expression was significantly associated with the poor prognosis of colon cancer patients. CRISPR-Cas9 knockout G6PD in colon cancer cell lines drastically reduces the anticancer activity of SUMO1 degraders. G6PD is a substrate of SUMO1 and SUMO1 conjugation enhances G6PD dimerization and enzymatic activity. By degradation of SUMO1, the small-molecule degraders reduce G6PD conjugation of SUMO1, its dimerization, and enzymatic activity, which sensitizes colon cancer cell lines to FOLFOX. The combination of SUMO1 degraders and FOLFOX synergically suppresses the growth of advanced colon cancer PDXs. In conclusion, the studies suggest the combination treatment of advanced colon cancer with SUMO1 degraders and FOLFOX.
Audience Take Away Notes:
- Introduction of therapeutic innovation of small-molecule degraders as novel anticancer drugs.
- Novel therapy of advanced colon cancer using SUMO1 degraders, alone or in combination with FOLFOX.
- G6PD as a therapeutic biomarker in the combination treatment of advanced colon cancer.
