RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition
Lishan Fang, Dane Ford-Roshon, Max Russo, Casey O’Brien, Xiaozhe Xiong, Carino Gurjao, Maximilien Grandclaudon, Srivatsan Raghavan, Steven M. Corsello, Steven A. Carr, Namrata D. Udeshi, James Berstler, Ewa Sicińska, Kimmie Ng, Marios Giannakis
Abstract
Abstract The RNF43 _p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43 _p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43 _p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43 659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43 _p.G659fs mutations. We find that RNF43 659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43 659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43 659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43 _p.G659fs mutant cancers.