Details

Autor(en) / Beteiligte

• Fang, Lishan
• Ford-Roshon, Dane
• Russo, Max
• O'Brien, Casey
• Xiong, Xiaozhe
• Gurjao, Carino
• Grandclaudon, Maximilien
• Raghavan, Srivatsan
• Corsello, Steven M
• Carr, Steven A
• Udeshi, Namrata D
• Berstler, James
• Sicinska, Ewa
• Ng, Kimmie
• Giannakis, Marios

Titel

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

Ist Teil von

• Nature communications, 2022-06, Vol.13 (1), p.3181-3181, Article 3181

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43 binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43 isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43 may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.