The LoF mutation of Znrf3/Rnf43 was reported to be oncogenic, and Porc inhibitors had shown a remarkable potency in this aspect.27,124,278 Unfortunately, the absence of Apc is likely to induce a Wnt ligand-independent signaling, so tumors with Apc LoF mutations may be resistant to Porc inhibitors.279 And Picco et al. reported that in a CRC cell line (VACO6) with RSPO3 fusion, long-term exposure (3 months) of a Porc inhibitor (LGK974) with incremental doses can induce drug resistance. Here, RNF43 is linked to colorectal carcinoma.