RNF43

RNF43 (Ring Finger Protein 43), a membrane-bound E3 ubiquitin ligase, plays a pivotal role in Wnt signaling regulation by ubiquitinating Frizzled receptors for lysosomal degradation, thereby suppressing pathway activity. It functionally overlaps with ZNRF3, another homologous E3 ligase. RNF43 mutations (frameshift/nonsense) are hallmark drivers in microsatellite-unstable cancers, notably colorectal (15-20%), pancreatic ductal adenocarcinoma (10%), and endometrial carcinomas. These loss-of-function mutations lead to Wnt/β-catenin pathway hyperactivation, driving tumorigenesis. Therapeutic strategies targeting RNF43-deficient tumors include PORCN inhibitors (e.g., ETC-159) to block Wnt ligand secretion and R-spondin (RSPO)-neutralizing antibodies (e.g., RG6139) exploiting synthetic lethality in RNF43-mutated cancers. Recent phase I trials demonstrated tolerability of anti-RSPO3 agents in colorectal cancer, with biomarker-driven trials ongoing.