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 Sicinska, Kimmie Ng and Marios Giannakis ()
Additional contact information
Lishan Fang: Harvard Medical School
Dane Ford-Roshon: Harvard Medical School
Max Russo: Harvard Medical School
Casey O’Brien: Harvard Medical School
Xiaozhe Xiong: Boston Children’s Hospital
Carino Gurjao: Harvard Medical School
Maximilien Grandclaudon: Harvard Medical School
Srivatsan Raghavan: Harvard Medical School
Steven M. Corsello: Harvard Medical School
Steven A. Carr: Broad Institute of MIT and Harvard
Namrata D. Udeshi: Broad Institute of MIT and Harvard
James Berstler: Broad Institute of MIT and Harvard
Ewa Sicinska: Harvard Medical School
Kimmie Ng: Harvard Medical School
Marios Giannakis: Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-12

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 RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-30794-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30794-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-30794-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().