Inappropriate increase in Wnt receptor activity due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 or R‐spondin fusions has recently been identified as a prominent driver of cancer development.[20, 21, 22] The antagonists targeting canonical Wnt receptors hold promise for treating these specific cancer subsets.[23, 24, 25] Thus, the development of synthetic LRP antagonists has great prospects for therapeutic applications. The gene discussed is RNF43; the disease is cancer.