RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition

The RNF43_G659fs mutation occurs frequently in colorectal cancer, however, its function remains poorly understood. In addition, there are no specific therapies directed against this alteration. In this study, we found that RNF43_G659fs is not a passenger mutation, but rather promotes cell growth independent of Wnt signaling. We performed a drug repurposing library screen and discovered that cells with RNF43_G659 mutations were selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yielded promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_G659fs mutations. We found that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination. Additionally, RNA-sequencing of RNF43659mut isogenic cells revealed decreased interferon signaling that may alter tumor immunity. Our findings suggest a novel therapeutic application for PI3K/mTOR inhibitors in treating RNF43_G659fs mutant cancers. Overall design: mRNA profiles of HT29-sgCtrl and HT29_RNF43_G659 mutations