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Nat Commun DOI:10.1038/s41467-022-30794-7

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

Publication TypeJournal Article
Year of Publication2022
AuthorsFang, L, Ford-Roshon, D, Russo, M, O'Brien, C, Xiong, X, Gurjao, C, Grandclaudon, M, Raghavan, S, Corsello, SM, Carr, SA, Udeshi, ND, Berstler, J, Sicinska, E, Ng, K, Giannakis, M
JournalNat Commun
Volume13
Issue1
Pages3181
Date Published2022 06 08
ISSN2041-1723
KeywordsCell Line, Tumor, Colorectal Neoplasms, Humans, Mutation, Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases
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 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.

DOI10.1038/s41467-022-30794-7
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35676246?dopt=Abstract

Alternate JournalNat Commun
PubMed ID35676246
PubMed Central IDPMC9177965
Grant ListC10674/A27140 / CRUK_ / Cancer Research UK / United Kingdom
U24 CA210986 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States
K08 CA230220 / CA / NCI NIH HHS / United States