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; Marios Giannakis

doi:10.1038/s41467-022-30794-7

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

Nat Commun. 2022 Jun 8;13(1):3181. doi: 10.1038/s41467-022-30794-7.

Authors

Lishan Fang^#^{1

2

3}, Dane Ford-Roshon^#^{1

2}, Max Russo^{1

2}, Casey O'Brien^{1

2}, Xiaozhe Xiong^{4

5}, Carino Gurjao^{1

2}, Maximilien Grandclaudon^{1

2}, Srivatsan Raghavan^{1

2}, Steven M Corsello^{1

2}, Steven A Carr², Namrata D Udeshi², James Berstler², Ewa Sicinska¹, Kimmie Ng¹, Marios Giannakis^{6

7}

Affiliations

¹ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Medical Research Center, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
⁴ Department of Urology, Boston Children's Hospital, Boston, MA, USA.
⁵ Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
⁶ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. marios_giannakis@dfci.harvard.edu.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA. marios_giannakis@dfci.harvard.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cell Line, Tumor
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Humans
Mutation
Phosphatidylinositol 3-Kinases* / genetics
TOR Serine-Threonine Kinases* / genetics
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism

Substances

RNF43 protein, human
Ubiquitin-Protein Ligases
MTOR protein, human
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding